Gene Summary

Gene:SOX4; SRY-box transcription factor 4
Aliases: CSS10, EVI16
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, such as syndecan binding protein (syntenin). The protein may function in the apoptosis pathway leading to cell death as well as to tumorigenesis and may mediate downstream effects of parathyroid hormone (PTH) and PTH-related protein (PTHrP) in bone development. The solution structure has been resolved for the HMG-box of a similar mouse protein. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:transcription factor SOX-4
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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

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: SOX4 (cancer-related)

Liu Y, Li F, Lai D, et al.
MicroRNA-140 inhibits proliferation and promotes apoptosis and cell cycle arrest of prostate cancer via degrading SOX4.
J BUON. 2019 Jan-Feb; 24(1):249-255 [PubMed] Related Publications
PURPOSE: To explore the regulatory roles of microRNA-140 and SOX4 in prostate cancer (PCa) tissues and paracancerous tissues, and their underlying mechanism.
METHODS: MicroRNA-140 expressions in PCa tissues, paracancerous tissues and PCa cell lines were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Proliferation, apoptosis and cell cycle of PCa cells after altering expressions of microRNA-140 and SOX4 were detected by MTT assay and flow cytometry, respectively. The regulatory effect of microRNA-140 on SOX4 was detected by Western blot and qRT-PCR. The binding condition of microRNA-140 on SOX4 was verified by luciferase reporter gene assay.
RESULTS: MicroRNA-140 was downregulated in PCa tissues compared to paracancerous tissues. In particular, lower expression of microRNA-140 was found in PCa with Grade I+II compared to Grade III+IV. In vitro, microRNA-140 expression was negatively correlated with proliferative and invasive abilities, while positively correlated with apoptosis of PCa cells. MicroRNA-140 promoted cell cycle arrest in G0/G1 phase. SOX4 expression was inhibited by microRNA-140 overexpression in PCa cells.
CONCLUSIONS: Downregulated microRNA-140 promotes proliferation and cell cycle arrest, but inhibits apoptosis of PCa cells. MicroRNA-140 inhibits PCa development via degrading SOX4.

Ding L, Zhao Y, Dang S, et al.
Circular RNA circ-DONSON facilitates gastric cancer growth and invasion via NURF complex dependent activation of transcription factor SOX4.
Mol Cancer. 2019; 18(1):45 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Circular RNAs (circRNAs) are a novel type of noncoding RNAs and play important roles in tumorigenesis, including gastric cancer (GC). However, the functions of most circRNAs remain poorly understood. In our study, we aimed to investigate the functions of a new circRNA circ-DONSON in GC progression.
METHODS: The expression of circ-DONSON in gastric cancer tissues and adjacent normal tissues was analyzed by bioinformatics method, qRT-PCR, Northern blotting and in situ hybridization (ISH). The effects of circ-DONSON on GC cell proliferation, apoptosis, migration and invasion were measured by using CCK8, colony formation, EdU, immunofluorescence (IF), FACS and Transwell assays. qRT-PCR and Western blotting were utilized to validate how circ-DONSON regulates SOX4 expression. ChIP, DNA fluorescence in situ hybridization (DNA-FISH) and DNA accessibility assays were used to investigate how circ-DONSON regulates SOX4 transcription. The interaction between circ-DONSON and NURF complex was evaluated by mass spectrum, RNA immunoprecipitation (RIP), pulldown and EMSA assays. Xenograft mouse model was used to analyze the effect of circ-DONSON on GC growth in vivo.
RESULTS: Elevated expression of circ-DONSON was observed in GC tissues and positively associated with advanced TNM stage and unfavorable prognosis. Silencing of circ-DONSON significantly suppressed the proliferation, migration and invasion of GC cells while promoting apoptosis. circ-DONSON was localized in the nucleus, recruited the NURF complex to SOX4 promoter and initiated its transcription. Silencing of the NURF complex subunit SNF2L, BPTF or RBBP4 similarly attenuated GC cell growth and increased apoptosis. circ-DONSON knockdown inhibited GC growth in vivo.
CONCLUSION: circ-DONSON promotes GC progression through recruiting the NURF complex to initiate SOX4 expression.

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.

Sun Z, Zhang T, Chen B
Long Non-Coding RNA Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) Promotes Proliferation and Metastasis of Osteosarcoma Cells by Targeting c-Met and SOX4 via miR-34a/c-5p and miR-449a/b.
Med Sci Monit. 2019; 25:1410-1422 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a functional long non-coding RNA involved in many biologic processes. The study was aimed to explore the functional roles of MALAT1 in osteosarcoma progression. MATERIAL AND METHODS A total of 76 osteosarcoma tissues and paired adjacent non-tumor tissues were collected from surgical resection. MALAT1, miRNAs, and genes mRNA expression levels were detected using quantitative real-time PCR (qRT-PCR). Protein expression level, cell proliferation, migration, and invasion were assessed using western blot, Cell Counting Kit-8 (CCK-8), wound-healing assay, and Matrigel invasion assay respectively. The target relationships among miRNAs, MALAT1, and mRNA were detected via dual-luciferase reporter assay. RESULTS We found that MALAT1 was frequently upregulated in osteosarcoma samples and cell lines and a high level of MALAT1 predicted poor overall survival in osteosarcoma patients. Knockdown of MALAT1 inhibited proliferation, migration, and invasion of osteosarcoma cells. Further study showed a positive correlation between MALAT1 and c-Met or SOX4 expression. Mechanistic investigations demonstrated that MALAT1, as a competing endogenous RNA (ceRNA), regulated osteosarcoma proliferation and metastasis through competitively binding to miR-34a/c-5p and miR-449a/b. CONCLUSIONS Taken together, our study illustrates a new regulatory mechanism for MALAT1 and may provide a novel therapeutic strategy for the treatment of osteosarcoma.

Zhao Y, Huang W, Kim TM, et al.
MicroRNA-29a activates a multi-component growth and invasion program in glioblastoma.
J Exp Clin Cancer Res. 2019; 38(1):36 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Glioblastoma is a malignant brain tumor characterized by rapid growth, diffuse invasion and therapeutic resistance. We recently used microRNA expression profiles to subclassify glioblastoma into five genetically and clinically distinct subclasses, and showed that microRNAs both define and contribute to the phenotypes of these subclasses. Here we show that miR-29a activates a multi-faceted growth and invasion program that promotes glioblastoma aggressiveness.
METHODS: microRNA expression profiles from 197 glioblastomas were analyzed to identify the candidate miRNAs that are correlated to glioblastoma aggressiveness. The candidate miRNA, miR-29a, was further studied in vitro and in vivo.
RESULTS: Members of the miR-29 subfamily display increased expression in the two glioblastoma subclasses with the worst prognoses (astrocytic and neural). We observed that miR-29a is among the microRNAs that are most positively-correlated with PTEN copy number in glioblastoma, and that miR-29a promotes glioblastoma growth and invasion in part by targeting PTEN. In PTEN-deficient glioblastoma cells, however, miR-29a nevertheless activates AKT by downregulating the metastasis suppressor, EphB3. In addition, miR-29a robustly promotes invasion in PTEN-deficient glioblastoma cells by repressing translation of the Sox4 transcription factor, and this upregulates the invasion-promoting protein, HIC5. Indeed, we identified Sox4 as the most anti-correlated predicted target of miR-29a in glioblastoma. Importantly, inhibition of endogenous miR-29a decreases glioblastoma growth and invasion in vitro and in vivo, and increased miR-29a expression in glioblastoma specimens correlates with decreased patient survival.
CONCLUSIONS: Taken together, these data identify miR-29a as a master regulator of glioblastoma growth and invasion.

Li Y, Tao C, Dai L, et al.
MicroRNA-625 inhibits cell invasion and epithelial-mesenchymal transition by targeting SOX4 in laryngeal squamous cell carcinoma.
Biosci Rep. 2019; 39(1) [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Laryngeal squamous cell carcinoma (LSCC) is a highly aggressive malignant cancer, but the molecular mechanisms underlying its development and progression remain largely elusive. The purpose of the present study is to investigate the expression profile and functional role of microRNA-625 (miR-625) in LSCC.
MATERIALS AND METHODS: LSCC tissues and adjacent normal tissues were collected from 86 LSCC patients. The expression levels of miR-625 and SOX4 mRNA in tissues and cells were detected by RT-qPCR analysis. The expression levels of SOX4 and EMT-related proteins were detected by western blot analysis.
RESULTS: The results demonstrated that miR-625 is significantly down-regulated in clinical LSCC tissues, and its low expression may be closely associated with unfavorable clinicopathological characteristics of LSCC patients. Overexpression of miR-625 significantly suppressed the proliferation, migration, invasion, and EMT of LSCC cells. Furthermore, SOX4 was validated as a direct target of miR-625 in LSCC cells, and rescue experiments suggested that restoration of SOX4 blocked the tumor suppressive role of miR-625 in LSCC cells.
CONCLUSIONS: Taken together, these findings highlighted a critical role of miR-625 in the pathogenesis of LSCC, and restoration of miR-625 could be considered as a potential therapeutic strategy against this fatal disease.

Vervoort SJ, de Jong OG, Roukens MG, et al.
Global transcriptional analysis identifies a novel role for SOX4 in tumor-induced angiogenesis.
Elife. 2018; 7 [PubMed] Free Access to Full Article Related Publications
The expression of the transcription factor

Bin C, Xiaofeng H, Wanzi X
The effect of microRNA-129 on the migration and invasion in NSCLC cells and its mechanism.
Exp Lung Res. 2018; 44(6):280-287 [PubMed] Related Publications
PURPOSE: To investigate the effect of microRNA-129 on the migration and invasion in (Non small cell lung cancer) NSCLC cells and involved mechanism.
MATERIALS AND METHODS: A549 cells were cultured and transfected with microRNA-129 (miR-129) mimic. Wound-healing assay and transwell assay were used to analyses the migration and invasion of A549 cells, respectively. The SOX4 expression changes were detected by qRT-PCR and Western blot. Dual-luciferase reporter assay was used to determine the binding site between miR-129 and the 3'-UTR of SOX4. A549 cells, miR-129 up-regulated A549 cells and miR-129 + SOX4 up-regulated A549 cells were treated with TGF-β in order to induce the epithelial-mesenchymal transition (EMT). The miR-129 and SOX4 after TGF-β treatment were measured. The EMT markers level changes were detected by western blot.
RESULTS: Up-regulation of miR-129 significantly inhibited the migration and invasion of A549 cells. miR-129 mimic transfection could reduce the mRNA and protein level of SOX4. Dual-luciferase reporter assay showed that miR-129 could bind to the 3'-UTR of SOX4. TGF-β induced EMT accompanied by the reduction of miR-129 and elevating of SOX4. Up-regulation of miR-129 could reverse the EMT marker changes caused by TGF-β, however, the SOX4 overexpression antagonized this effect of miR-129.
CONCLUSIONS: miR-129 could suppress the migration and invasion of A549 cells. The potential mechanism may be that miR-129 inhibit EMT via targeting SOX4.

Lei X, Li L, Duan X
Long non-coding RNA ABHD11-AS1 promotes colorectal cancer development through regulation of miR-133a/SOX4 axis.
Biosci Rep. 2018; 38(6) [PubMed] Free Access to Full Article Related Publications
Recently, lncRNA has been verified to regulate the development and progression of tumor. LncRNA ABHD11-AS1 has been proven to serve as an oncogene in several cancers. However, the role of ABHD11-AS1 in colorectal cancer remains totally unknown. In the present study, qRT-PCR assay revealed that ABHD11-AS1 expression was markedly higher in colorectal cancer tissues and cell lines. In addition, patients who displayed overexpression of ABHD11-AS1 showed a significantly poorer progression free survival (PFS) and overall survival (OS) by Kaplan-Meier analysis. Loss-of-function experiments suggested that silencing of ABHD11-AS1 expression could significantly reduce the proliferation, colony formation, migration and invasion of colorectal cancer cells, and increase cell apoptosis. Moreover, bioinformatics analysis, biotin pull-down assay, luciferase reporter assay, and RIP assay disclosed that ABHD11-AS1 straightly interacted with miR-133a. We also found that SOX4 was a downstream target of miR-133a and ABHD11-AS1 subsequently exerted its biological effects via modulating the expression of SOX4 in colorectal cancer cells. Collectively, these findings manifested that the ABHD11-AS1/miR-133a/SOX4 axis may be a cogitable and promising therapeutic target for colorectal cancer.

Sun X, Liu H, Li T, Qin L
MicroRNA‑339‑5p inhibits cell proliferation of acute myeloid leukaemia by directly targeting SOX4.
Mol Med Rep. 2018; 18(6):5261-5269 [PubMed] Related Publications
In recent decades, microRNAs (miRNAs) have been considered novel gene regulators. Dysregulated miRNAs serve crucial roles in the formation and progression of acute myeloid leukaemia (AML). Therefore, the roles of differentially expressed miRNAs in AML require extensive investigation to obtain insight into the treatment of patients with AML. The present study demonstrated significant miR‑339‑5p downregulation in AML samples and cell lines. miR‑339‑5p overexpression attenuated AML cell proliferation by inducing cell cycle arrest and promoting cell apoptosis. Additionally, sex‑determining region Y‑related high‑mobility group box 4 (SOX4) was identified as a direct target gene of miR‑339‑5p in AML. Furthermore, SOX4 expression was significantly upregulated in AML samples; this upregulation was inversely correlated with the expression levels of miR‑339‑5p. Additionally, a series of rescue experiments demonstrated that SOX4 resumption reversed the effects of miR‑339‑5p overexpression on cell proliferation, cycle status and apoptosis of AML. In conclusion, miR‑339‑5p may serve its antiproliferative role in AML by directly targeting SOX4, which suggests that miR‑339‑5p may be considered an effective novel therapeutic target for treating patients with such an aggressive haematological malignancy.

Sun H, Li Y, Kong H, et al.
Dysregulation of KCNQ1OT1 promotes cholangiocarcinoma progression via miR-140-5p/SOX4 axis.
Arch Biochem Biophys. 2018; 658:7-15 [PubMed] Related Publications
It is commonly recognized that aberrant expression of long non-coding RNAs (lncRNAs) is an important cause of cancer progression. The oncogenic property of KCNQ1OT1 has been identified in several malignant tumors. Here, we decided to explore the biological function and molecular mechanism of KCNQ1OT1 in cholangiocarcinoma (CCA). The expression conditions of KCNQ1OT1 in different tissues and cell lines were examined with qRT-PCR analysis. As expected, KCNQ1OT1 was highly expressed in CCA tissues and cell lines. Results of functional assays revealed the oncogenic function of KCNQ1OT in cholangiocarcinoma progression. The positive effect of KCNQ1OT1 on cell proliferation, invasion and epithelial-mesenchymal transition was identified by performing MTT assay, colony formation assay, transwell invasion assay and western blotting. Whereas, the negative effect of KCNQ1OT1 on the cell apoptosis was tested with flow cytometry analysis. Mechanism investigation revealed that KCNQ1OT1 can act as a ceRNA to improve CCA progression by regulating miR-140-5p/SOX4 axis. Recue assays were conducted to demonstrate the actual effects of KCNQ1OT1-miR-140-5p-SOX4 pathway on CCA progression.

Vervoort SJ, Lourenço AR, Tufegdzic Vidakovic A, et al.
SOX4 can redirect TGF-β-mediated SMAD3-transcriptional output in a context-dependent manner to promote tumorigenesis.
Nucleic Acids Res. 2018; 46(18):9578-9590 [PubMed] Free Access to Full Article Related Publications
Expression of the transcription factor SOX4 is often elevated in human cancers, where it generally correlates with tumor-progression and poor-disease outcome. Reduction of SOX4 expression results in both diminished tumor-incidence and metastasis. In breast cancer, TGF-β-mediated induction of SOX4 has been shown to contribute to epithelial-to-mesenchymal transition (EMT), which controls pro-metastatic events. Here, we identify SMAD3 as a novel, functionally relevant SOX4 interaction partner. Genome-wide analysis showed that SOX4 and SMAD3 co-occupy a large number of genomic loci in a cell-type specific manner. Moreover, SOX4 expression was required for TGF-β-mediated induction of a subset of SMAD3/SOX4-co-bound genes regulating migration and extracellular matrix-associated processes, and correlating with poor-prognosis. These findings identify SOX4 as an important SMAD3 co-factor controlling transcription of pro-metastatic genes and context-dependent shaping of the cellular response to TGF-β. Targeted disruption of the interaction between these factors may have the potential to disrupt pro-oncogenic TGF-β signaling, thereby impairing tumorigenesis.

Liu E, Sun X, Li J, Zhang C
miR‑30a‑5p inhibits the proliferation, migration and invasion of melanoma cells by targeting SOX4.
Mol Med Rep. 2018; 18(2):2492-2498 [PubMed] Related Publications
MicroRNA (miR)‑30a‑5p has been reported to suppress the progression of hepatocellular cancer, renal cell carcinoma, oral cancer and gastric cancer. However, whether miR‑30a‑5p is involved in the regulation of melanoma remains unclear. The present study revealed that miR‑30a‑5p was downregulated in melanoma tissues and cell lines. Overexpression of miR‑30a‑5p significantly inhibited the proliferation, migration and invasion of melanoma cells in vitro. In addition, ectopic expression of miR‑30a‑5p delayed tumor growth in vivo. In terms of mechanism, miR‑30a‑5p targeted sex determining region Y‑box 4 (SOX4) and impeded the expression of SOX4 in melanoma cells. In addition, SOX4 was upregulated in melanoma tissues and cell lines when compared with normal tissues or cells. Furthermore, overexpression of SOX4 significantly rescued the proliferation, migration and invasion of melanoma cells transfected with miR‑30a‑5p mimics. Taken together, the results of the present study demonstrated that miR‑30a‑5p suppressed the proliferation, migration and invasion of melanoma cells in SOX4‑dependent manner.

Soliman B, Salem A, Ghazy M, et al.
Bioinformatics functional analysis of let-7a, miR-34a, and miR-199a/b reveals novel insights into immune system pathways and cancer hallmarks for hepatocellular carcinoma.
Tumour Biol. 2018; 40(5):1010428318773675 [PubMed] Related Publications
Let-7a, miR-34a, and miR-199 a/b have gained a great attention as master regulators for cellular processes. In particular, these three micro-RNAs act as potential onco-suppressors for hepatocellular carcinoma. Bioinformatics can reveal the functionality of these micro-RNAs through target prediction and functional annotation analysis. In the current study, in silico analysis using innovative servers (miRror Suite, DAVID, miRGator V3.0, GeneTrail) has demonstrated the combinatorial and the individual target genes of these micro-RNAs and further explored their roles in hepatocellular carcinoma progression. There were 87 common target messenger RNAs (p ≤ 0.05) that were predicted to be regulated by the three micro-RNAs using miRror 2.0 target prediction tool. In addition, the functional enrichment analysis of these targets that was performed by DAVID functional annotation and REACTOME tools revealed two major immune-related pathways, eight hepatocellular carcinoma hallmarks-linked pathways, and two pathways that mediate interconnected processes between immune system and hepatocellular carcinoma hallmarks. Moreover, protein-protein interaction network for the predicted common targets was obtained by using STRING database. The individual analysis of target genes and pathways for the three micro-RNAs of interest using miRGator V3.0 and GeneTrail servers revealed some novel predicted target oncogenes such as SOX4, which we validated experimentally, in addition to some regulated pathways of immune system and hepatocarcinogenesis such as insulin signaling pathway and adipocytokine signaling pathway. In general, our results demonstrate that let-7a, miR-34a, and miR-199 a/b have novel interactions in different immune system pathways and major hepatocellular carcinoma hallmarks. Thus, our findings shed more light on the roles of these miRNAs as cancer silencers.

Cheng Q, Du J, Xie L, et al.
Inhibition of SOX4 induces melanoma cell apoptosis via downregulation of NF-κB p65 signaling.
Oncol Rep. 2018; 40(1):369-376 [PubMed] Related Publications
SOX4 (SRY Box 4) has attracted attention due to its important effects on cell growth, proliferation and apoptosis, among other cellular processes. However, the role of SOX4 in melanoma cell apoptosis remains unclear. In the present study, we investigated whether inhibition of SOX4 induces melanoma cell apoptosis, and explored the possible mechanism involving the NF-κB signaling pathway. SOX4 was knocked down using a lentivirus in melanoma A2058 and SK-MEL-5 cell lines. Cell proliferation was measured by MTT assay. Apoptosis was determined by flow cytometry. Western blotting was performed to detect the protein levels of SOX4, p65 and apoptosis-related proteins, such as PARP, Bcl-2, Bax and survivin. Quantitative real-time PCR (qRT-PCR) was used to examine the mRNA levels of SOX4 and p65. To determine whether SOX4 is able to bind to the promoter of p65, a CHIP-PCR assay was performed. Our data demonstrated that SOX4 knockdown significantly induced apoptosis in melanoma cells, which was accompanied by increases in cleaved PARP and Bax, and decreases in Bcl-2 and survivin. The expression of p65 was also decreased in SOX4-knockdown melanoma cells. The CHIP-PCR assay indicated that SOX4 was able to bind to the promoter region of p65. We also observed that apoptosis in SOX4-knockdown and p65-overexpressing A2058 cells was much lower than that in SOX4-knockdown alone cells. This revealed that the overexpression of p65 partially reversed SOX4 downregulation-induced apoptosis. In conclusion, our results demonstrated that inhibition of SOX4 markedly induced melanoma cell apoptosis via downregulation of the NF-κB signaling pathway, which thus may be a novel approach for the treatment of melanoma.

Pan L, Meng L, Liang F, Cao L
miR‑188 suppresses tumor progression by targeting SOX4 in pediatric osteosarcoma.
Mol Med Rep. 2018; 18(1):441-446 [PubMed] Related Publications
microRNA‑188 (miR‑188) acts as a tumor suppressor in various types of human cancer, including glioma, oral squamous cell carcinoma and hepatocellular carcinoma. However, the function and mechanism of miR‑188 in pediatric osteosarcoma (OS) have yet to be investigated. In the present study reverse transcription‑quantitative polymerase chain reaction revealed that miR‑188 expression was significantly downregulated in pediatric OS tissues and cell lines. miR‑188 overexpression markedly suppressed OS cell proliferation, migration and invasion, and induced cellular apoptosis. An in vivo assay demonstrated that miR‑188 overexpression inhibited tumor growth. miR‑188 targeted SOX4 to regulate its expression. miR‑188 expression was inversely correlated with SOX4 in pediatric OS tissues. SOX4 restoration abrogated the inhibitory effects of miR‑188 on OS cells. The results of the present study indicated that miR‑188 suppressed pediatric OS progression by targeting SOX4.

Liu Y, Wang Y, Yao D, Cui D
LncSOX4 serves an oncogenic role in the tumorigenesis of epithelial ovarian cancer by promoting cell proliferation and inhibiting apoptosis.
Mol Med Rep. 2018; 17(6):8282-8288 [PubMed] Free Access to Full Article Related Publications
Epithelial ovarian cancer is one of the primary causes of gynecological cancer mortality. Increasing evidence has suggested that long non‑coding RNAs (lncRNAs) may serve a pivotal role in cancer development. To determine whether Lnc SRY‑box 4 (SOX4), an lncRNA, promotes the self‑renewal of liver tumor cells and contributes to the development of epithelial ovarian cancer, the present study investigated the expression of LncSOX4 in clinical epithelial ovarian cancer tissues and non‑cancer controls by reverse transcription‑quantitative polymerase chain reaction analysis. In addition, siRNA targeting LncSOX4 was designed and transfected into epithelial ovarian cancer cells to further assess the effect of knocking out LncSOX4 on cellular apoptosis, cell viability, proliferation and the cell cycle. The results demonstrated that the LncSOX4 expression level was significantly upregulated in epithelial ovarian cancer tissues (3.98 vs. 1.71, P<0.001). Silencing LncSOX4 in the SKOV3 and OVCAR3 cell lines significantly impaired cell proliferation (P<0.001). Cell cycle assays revealed that the proportion of cells in the G0/G1 phase increased significantly, whereas those in the S phase and G2/M phase decreased. Apoptosis rate additionally increased following knockdown of LncSOX4 in the two cell lines. Furthermore, it was observed that an increased LncSOX4 expression level was positively associated with larger tumor sizes, more advanced tumor grade and more distant metastases.

Kuipers AJ, Middelbeek J, Vrenken K, et al.
TRPM7 controls mesenchymal features of breast cancer cells by tensional regulation of SOX4.
Biochim Biophys Acta Mol Basis Dis. 2018; 1864(7):2409-2419 [PubMed] Related Publications
Mechanically induced signaling pathways are important drivers of tumor progression. However, if and how mechanical signals affect metastasis or therapy response remains poorly understood. We previously found that the channel-kinase TRPM7, a regulator of cellular tension implicated in mechano-sensory processes, is required for breast cancer metastasis in vitro and in vivo. Here, we show that TRPM7 contributes to maintaining a mesenchymal phenotype in breast cancer cells by tensional regulation of the EMT transcription factor SOX4. The functional consequences of SOX4 knockdown closely mirror those produced by TRPM7 knockdown. By traction force measurements, we demonstrate that TRPM7 reduces cytoskeletal tension through inhibition of myosin II activity. Moreover, we show that SOX4 expression and downstream mesenchymal markers are inversely regulated by cytoskeletal tension and matrix rigidity. Overall, our results identify SOX4 as a transcription factor that is uniquely sensitive to cellular tension and indicate that TRPM7 may contribute to breast cancer progression by tensional regulation of SOX4.

Wang Y, Xie J, Liu W, et al.
Lidocaine sensitizes the cytotoxicity of 5-fluorouacil in melanoma cells
Pharmazie. 2017; 72(11):663-669 [PubMed] Related Publications
Lidocaine is a well-documented local anesthetic that has been reported to sensitize the cytotoxicity of cisplatin in cancer cells. However, little information is available concerning whether lidocaine sensitizes the cytotoxicity of 5-fluorouracil (5-FU) in melanoma cells. The study was aimed to explore the effects and mechanisms of lidocaine on the sensitivity to 5-FU in the melanoma cell line SK-MEL-2. Cell viability and apoptosis were analyzed after administration of different concentrations of lidocaine, 5-FU, or the combinations. Expression of microRNA (miR)-493 was assessed following lidocaine administration. The target genes of miR-493 were verified by luciferase reporter assay, PCR, and Western blot. The effects of abnormal expression of miR-493 and/or SRY-Box 4 (SOX4) on cell viability, apoptosis, and key proteins in phosphatidylinositol-3-kinase (PI3K)/AKT and the Smad pathways were detected. The effects of (0-100 uM) lidocaine on cell viability and apoptosis was not obvious; however, lidocaine could significantly increase the cell viability and inhibit apoptosis in 5-FU-treated cells. In addition, lidocaine induced upregulation of miR-493 in a dose-dependent manner, and we confirmed that the effects of miR-493 on the sensitivity were by upregulating miR-493. Moreover, we verified that Sox4 was a target of miR-493, and Sox4 overexpression decreased the sensitivity to 5-FU. Besides, Sox4 overexpression increased the levels of p-PI3K, p-AKT, p-Smad2 and p-Smad3, and Sox4 suppression showed contrary results. Our results suggest that lidocaine sensitizes the cytotoxicity of 5-FU in melanoma cells via upregulation of miR-493, which might be involved in SOX4-mediated PI3K/AKT and Smad pathways.

Tian Z, Yang G, Jiang P, et al.
Long non-coding RNA Sox4 promotes proliferation and migration by activating Wnt/β-catenin signaling pathway in osteosarcoma.
Pharmazie. 2017; 72(9):537-542 [PubMed] Related Publications
Osteosarcoma is a bone tumor without effective treatment in the world. Recently, long non-coding RNAs (lncRNAs) are considered as essential regulators in cancer progression. LncSox4 plays crucial roles in liver tumor-initiating cells self-renewal and tumor initiation. However, the effect of lncSox4 in osteosarcoma remains largely unclear. Quantitative real-time PCR (qRT-PCR) and Northern blot were performed to detect lncSox4 expressions in osteosarcoma. The functions of lncSox4 in osteosarcoma were determined using cell viability and migration assays. In addition, the proteins associated with lncSox4 were further evaluated by western blot. We found that lncSox4 was expressed highly in U-20S and Mg63 cells and osteosarcoma tumor tissues (all P < 0.001). LncSox4 silencing attenuated but lncSox4 overexpression promoted cell viability (all P < 0.001) and migration (P < 0.01) in the Mg63 cells. Next, we found lncSox4 regulation of osteosarcoma is involved in β-catenin, and overexpression of lncSox4 could stable β-catenin expression. Further, Wnt agonist CID11210285 completely abolished the decrease of Mg63 cells viability induced by lncSox4 silencing when cells cultured for 3 and 4 days (both P < 0.01), while Wnt inhibitor IWP-3 abolished the increase of Mg63 cells viability induced by overexpression of lncSox4 after treatment for 2 (P < 0.01), 3 (P < 0.001) and 4 (P < 0.01) days. Our study offers evidence for the first time that lncSox4 plays a positive role in osteosarcoma development and progression, and could act as a potential prognostic and therapy biomarker.

Li G, Liu K, Du X
Long Non-Coding RNA TUG1 Promotes Proliferation and Inhibits Apoptosis of Osteosarcoma Cells by Sponging miR-132-3p and Upregulating SOX4 Expression.
Yonsei Med J. 2018; 59(2):226-235 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Long non-coding RNA taurine upregulated gene 1 (TUG1) is reported to be a vital regulator of the progression of various cancers. This study aimed to explore the exact roles and molecular mechanisms of TUG1 in osteosarcoma (OS) development.
MATERIALS AND METHODS: Real-time quantitative PCR was applied to detect the expressions of TUG1 and microRNA-132-3p (miR-132-3p) in OS tissues and cells. Western blot was performed to measure protein levels of sex determining region Y-box 4 (SOX4). Cell viability was assessed using XTT assay. Cell apoptosis was evaluated using flow cytometry and caspase-3 activity detection assays. Bioinformatics analysis and luciferase reporter experiments were employed to confirm relationships among TUG1, miR-132-3p, and SOX4.
RESULTS: TUG1 was highly expressed in human OS tissues, OS cell lines, and primary OS cells. TUG1 knockdown hindered proliferation and induced apoptosis in human OS cell lines and primary OS cells. Moreover, TUG1 inhibited miR-132-3p expression by direct interaction, and introduction of miR-132-3p inhibitor partly abrogated the effect of TUG1 knockdown on the proliferation and apoptosis of OS cells. Furthermore, SOX4 was validated as a target of miR-132-3p. Further functional analyses revealed that miR-132-3p inhibited proliferation and induced apoptosis of OS cells, while this effect was greatly abated following SOX4 overexpression. Moreover, TUG1 knockdown suppressed proliferation and promoted apoptosis by upregulating miR-132-3p and downregulating SOX4 in primary OS cells.
CONCLUSION: TUG1 facilitated proliferation and suppressed apoptosis by regulating the miR-132-3p/SOX4 axis in human OS cell lines and primary OS cells. This finding provides a potential target for OS therapy.

Dong X, Chen R, Lin H, et al.
lncRNA BG981369 Inhibits Cell Proliferation, Migration, and Invasion, and Promotes Cell Apoptosis by SRY-Related High-Mobility Group Box 4 (SOX4) Signaling Pathway in Human Gastric Cancer.
Med Sci Monit. 2018; 24:718-726 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Human gastric cancer (GC) is a leading primary cause of cancer-associated deaths in both males and females worldwide. However, there are few effective diagnostic and therapeutic measures for GC patients due to the complicated underlying mechanisms of GC. Recently, increasing research has indicated that lncRNAs may play a critical role in the progression of GC. MATERIAL AND METHODS AI769947, AK054978, DB077273, BG981369, AK054588, and AF131784 expressions were analyzed by qRT-PCR assay in GC tissues and corresponding normal tissues (n=44). BG981369 expression was detected by qRT-PCR assay in GC cells. BG981369 was overexpressed and silenced in AGS and SNU-5 cells. The proliferation ability was detected by MTT and colony formation assays. Cell cycle distribution and cell apoptosis rate were analyzed by flow cytometry. The migration and invasion abilities were measured by Transwell assay. In addition, SOX4 expression was analyzed by qRT-PCR in GC tissues. The correlation between SOX4 and BG981369 was analyzed by Pearson analysis. RESULTS The results indicated that lncRNA BG981369 was significantly higher in GC tissues than in normal tissues. Overexpression of BG981369 inhibited the proliferation, migration, and invasion and promoted apoptosis of gastric adenocarcinoma (AGS) cells, and silencing of BG981369 promoted proliferation, migration, and invasion, and inhibited cell apoptosis of SNU-5 cells. Furthermore, we found that SOX4 may act as a downstream mediator of BG981369, suggesting that BG981369 inhibits proliferation, migration, and invasion, and promotes apoptosis by targeting SOX4 in the GC cell lines. CONCLUSIONS Our results suggest that BG981369 and SOX4 are potentially effective therapeutic targets for GC.

Bhattaram P, Muschler G, Wixler V, Lefebvre V
Inflammatory Cytokines Stabilize SOXC Transcription Factors to Mediate the Transformation of Fibroblast-Like Synoviocytes in Arthritic Disease.
Arthritis Rheumatol. 2018; 70(3):371-382 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Fibroblast-like synoviocytes (FLS) produce key synovial fluid and tissue components to ensure joint integrity under healthy conditions, whereas they become cancer-like and aggressively contribute to joint degeneration in inflammatory arthritis. The aim of this study was to determine whether the SOXC transcription factors SOX4 and SOX11, whose functions are critical in joint development and many cancer types, contribute to FLS activities under normal and inflammatory conditions.
METHODS: We inactivated the SOXC genes in FLS from adult mice and studied the effect on joint homeostasis and tumor necrosis factor (TNF)-induced arthritis. We used primary cells and synovial biopsy specimens from arthritis patients to analyze the interactions between inflammatory signals and SOXC proteins.
RESULTS: Postnatal inactivation of the SOXC genes had no major effect on joint integrity in otherwise healthy mice. However, it hampered synovial hyperplasia and joint degeneration in transgenic mice expressing human TNF. These effects were explained by the ability of SOX4/11 to amplify the pathogenic impact of TNF on FLS by increasing their survival and migration. SOXC RNA levels were not changed by TNF and other proinflammatory cytokines, but SOXC proteins were strongly stabilized and able to potentiate the TNF-induced up-regulation of genes involved in FLS transformation. Substantiating the relevance of these findings in human disease, SOXC protein levels, but not RNA levels, were significantly higher in inflamed synovium than in noninflamed synovium from arthritis patients.
CONCLUSION: SOXC proteins are targets and pivotal mediators of proinflammatory cytokines during FLS transformation in arthritic diseases. Targeting of these proteins could thus improve current strategies to treat arthritic diseases and possibly other inflammatory diseases.

Mattes K, Berger G, Geugien M, et al.
CITED2 affects leukemic cell survival by interfering with p53 activation.
Cell Death Dis. 2017; 8(10):e3132 [PubMed] Free Access to Full Article Related Publications
CITED2 (CBP/p300-interacting-transactivator-with-an-ED-rich-tail 2) is a regulator of the acetyltransferase CBP/p300 and elevated CITED2 levels are shown in a number of acute myeloid leukemia (AML). To study the in vivo role of CITED2 in AML maintenance, AML cells were transduced with a lentiviral construct for RNAi-mediated knockdown of CITED2. Mice transplanted with CITED2-knockdown AML cells (n=4) had a significantly longer survival compared to mice transplanted with control AML cells (P<0.02). In vitro, the reduction of CITED2 resulted in increased p53-mediated apoptosis and CDKN1A expression, whereas BCL2 levels were reduced. The activation of p53 upon CITED2 knockdown is not a direct consequence of increased CBP/p300-activity towards p53, since no increased formation of CBP/p300/p53 complexes was demonstrated and inhibition of CBP/p300-activity could not rescue the phenotype of CITED2-deficient cells. Instead, loss of CITED2 had an inhibitory effect on the AKT-signaling pathway, which was indicated by decreased levels of phosphorylated AKT and altered expression of the AKT-pathway regulators PHLDA3 and SOX4. Notably, simultaneous upregulation of BCL2 or downregulation of the p53-target gene PHLDA3 rescued the apoptotic phenotype in CITED2-knockdown cells. Furthermore, knockdown of CITED2 led to a decreased interaction of p53 with its inhibitor MDM2, which results in increased amounts of total p53 protein. In summary, our data indicate that CITED2 functions in pathways regulating p53 activity and therefore represents an interesting target for AML therapy, since de novo AML cases are characterized by an inactivation of the p53 pathway or deregulation of apoptosis-related genes.

Chen D, Hu C, Wen G, et al.
DownRegulated SOX4 Expression Suppresses Cell Proliferation, Migration, and Induces Apoptosis in Osteosarcoma In Vitro and In Vivo.
Calcif Tissue Int. 2018; 102(1):117-127 [PubMed] Related Publications
The SOX4 transcription factor is involved in various cellular processes, such as embryonic development and differentiation. Deregulated expression of Sox4 in several human cancers has been reported to date, but its biological functions in the progression of osteosarcoma remain unclear. In this study, we found that the expression levels of SOX4 protein were significantly higher in high-grade osteosarcoma tissues and metastatic osteosarcoma tissues. Its overexpression was associated with poor prognosis in osteosarcoma. Knockdown of the SOX4 gene in the osteosarcoma cell lines resulted in decreased cell proliferation, migration, invasion, and induced apoptosis. After SOX4 gene silencing, the protein expression levels of Bax, Caspase-3, and P53 in osteosarcoma cells were significantly elevated, while the protein expression levels of Bcl-2, MMP2, and MMP9 were obviously decreased. In vivo analysis in nude mice further confirmed that knockdown of SOX4 suppressed tumor growth. In conclusion, SOX4 appears to be an important tumor oncogene in the regulation of osteosarcoma cell proliferation, apoptosis, and invasion, and it may be a potential target for effective osteosarcoma therapy.

Hu B, Zhang H, Wang Z, et al.
LncRNA CCAT1/miR-130a-3p axis increases cisplatin resistance in non-small-cell lung cancer cell line by targeting SOX4.
Cancer Biol Ther. 2017; 18(12):974-983 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Colon cancer-associated transcript-1 (CCAT1) has been demonstrated to act as an oncogene and promote chemoresistance in several cancers. However, little is known about the underlying mechanism of CCAT1 in cisplatin (DDP) resistance of non-small-cell lung cancer (NSCLC) cells.
METHODS: qRT-PCR was performed to detect the expression levels of CCAT, miR-130a-3p, or sex-determining region Y-box 4 (SOX4) mRNA. Luciferase reporter assay, RNA immunoprecipitation (RIP), and qRT-PCR analysis were carried out to explore the potential targets of CCAT1 or miR-130a-3p. Effect of CCAT1, miR-130a-3p, or SOX4 on IC
RESULTS: CCAT1 and SOX4 were up-regulated, and miR-130a-3p was down-regulated in DDP-resistant NSCLC cells compared with their parental NSCLC cells. CCAT1 directly interacted with miR-130a-3p and negatively regulated miR-130a-3p expression. CCAT1 contributed to DDP resistance of A549/DDP cells by down-regulating miR-130a-3p. miR-130a-3p was found to directly target SOX4 to suppress its expression. SOX4 knockdown reversed miR-130a-3p-inhibition-induced increase of DDP resistance and ABCG2 expression in NSCLC cells. Exogenous expression of SOX4 abrogated CCAT1-knockdown-mediated decrease of DDP resistance and ABCG2 expression in DDP-resistant NSCLC cells.
CONCLUSION: CCAT1/miR-130a-3p axis enhanced DDP resistance of NSCLC cells by targeting SOX4, providing potential targets to overcome DDP resistance and improve efficacy of chemotherapy for patients with NSCLC.

Dong F, Zhang G, Zhang X, et al.
Aberrantly expressed transcription factors C/EBP and SOX4 have positive effects in the development of chronic myeloid leukemia.
Mol Med Rep. 2017; 16(5):7131-7137 [PubMed] Related Publications
The aim of the present study was to examine the expression and significance of CCAAT/enhancer binding protein α (C/EBPα) and SRY‑related high mobility group box containing transcription factor 4 (SOX4) in chronic myeloid leukemia (CML). Bone marrow samples were collected from patients with CML, and peripheral blood mononuclear cells were collected from healthy controls. Protein and mRNA were extracted from the collected samples, and analyzed using western blotting and reverse transcription‑quantitative polymerase chain reaction analyses, respectively. Spearman's method was used to evaluate the correlation between the expression levels of these two genes, with P<0.05 considered to indicate a statistically significant difference. A total of 79 patients, including 57 patients with newly diagnosed CML and 22 patients treated with imatinib therapy, and 30 controls were enrolled. The expression of SOX4 was upregulated in the patients with CML, whereas the expression of C/EBPα was downregulated (P<0.05). However, no differences were observed among the chronic, accelerated and blastic CML phases, respectively (P>0.05). In addition, no associations were found between the changes in expression and age, gender, white blood cells or the expression of breakpoint cluster region/abelson in patients (P>0.05). However, the expression of SOX4 was negatively correlated with the expression of C/EBPα (P<0.01). Following imatinib treatment, the expression of SOX4 was downregulated in the progression‑free patients, but upregulated in the blastic phase patients, whereas the expression of C/EBPα showed the opposite trend. Therefore, C/EBPα and SOX4 were important and negatively associated with the process of CML, and the C/EBPα‑SOX4 axis may be a novel potential therapeutic target for the treatment of CML.

Chiba R, Akiya M, Hashimura M, et al.
ALK signaling cascade confers multiple advantages to glioblastoma cells through neovascularization and cell proliferation.
PLoS One. 2017; 12(8):e0183516 [PubMed] Free Access to Full Article Related Publications
Anaplastic lymphoma kinase (ALK), which is a receptor tyrosine kinase, is essentially and transiently expressed in the developing nervous system. Here we examined the functional role of the ALK gene in glioblastomas (GBMs). In clinical samples of GBMs, high ALK expression without gene rearrangements or mutations was frequently observed in perivascular lesions, in contrast to the relatively low expression in the perinecrotic areas, which was positively correlated with N-myc and phosphorylated (p) Stat3 scores and Ki-67 labeling indices. ALK immunoreactivity was also found to be associated with neovascular features including vascular co-option and vascular mimicry. In astrocytoma cell lines, cells stably overexpressing full-length ALK showed an increase in expression of pStat3 and pAkt proteins, as well as hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor-A (VEGF-A) mRNAs, in contrast to cells with knockdown of endogenous ALK which showed decreased expression of these molecules. Transfection of the constitutively active form of Stat3 induced an increase in HIF-1α promoter activity, and the overexpression of HIF-1α in turn resulted in enhancement of VEGF-A promoter activity. In addition, cells with overexpression or knockdown of ALK also showed a tendency toward increased and decreased proliferation, respectively, through changes in expression of pAkt and pStat3. Finally, ALK promoter was significantly activated by transfection of Sox4 and N-myc, which are known to contribute to neuronal properties. These findings therefore suggest that N-myc/Sox4-mediated ALK signaling cascades containing Stat3, Akt, HIF-1α, and VEGF-A confer multiple advantages to tumor growth through alterations in neovascularization and cell proliferation in GBMs.

Wang H, Huo X, Yang XR, et al.
STAT3-mediated upregulation of lncRNA HOXD-AS1 as a ceRNA facilitates liver cancer metastasis by regulating SOX4.
Mol Cancer. 2017; 16(1):136 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Several of the thousands of human long noncoding RNAs (lncRNAs) have been functionally characterized, yet their potential involvement in hepatocellular carcinoma (HCC) remains poorly understood.
METHODS: LncRNA-HOXD-AS1 was identified by microarray and validated by real-time PCR. The clinicopathological significance of HOXD-AS1 was analyzed by Kaplan-Meier method. Chromatin immunoprecipitation was conducted to examine the mechanism of HOXD-AS1 upregulation. The role of HOXD-AS1 in HCC cells was assessed both in vitro and in vivo. ceRNA function of HOXD-AS1 was evaluated by RNA immunoprecipitation and biotin-coupled miRNA pull down assays.
RESULTS: In this study, we found that HOXD-AS1 was significantly upregulated in HCC tissues. Clinical investigation demonstrated high expression level of HOXD-AS1 was associated with poor prognosis and high tumor node metastasis stage of HCC patients, and was an independent risk factor for survival. Moreover, our results revealed that STAT3 could specifically interact with the promoter of HOXD-AS1 and activate HOXD-AS1 transcription. Knockdown of HOXD-AS1 significantly inhibited migration and invasion of HCC cells in vitro and distant lung metastasis in vivo. Additionally, HOXD-AS1 was enriched in the cytoplasm, and shared miRNA response elements with SOX4. Overexpression of HOXD-AS1 competitively bound to miR-130a-3p that prevented SOX4 from miRNA-mediated degradation, thus activated the expression of EZH2 and MMP2 and facilitated HCC metastasis.
CONCLUSIONS: In summary, HOXD-AS1 is a prognostic marker for HCC patients and it may play a pro-metastatic role in hepatocarcinogenesis.

Tang T, Huan L, Zhang S, et al.
MicroRNA-212 functions as a tumor-suppressor in human non-small cell lung cancer by targeting SOX4.
Oncol Rep. 2017; 38(4):2243-2250 [PubMed] Related Publications
Increasing evidence has revealed that aberrant expression of miRNAs contributes to non-small cell lung cancer (NSCLC) development and progression. However, the roles and mechanisms of various miRNAs in NSCLC remain to be determined. In the present study, we confirmed that reduced miR-212 expression was present in NSCLC tissues and cell lines. Our clinical analysis revealed that the reduced miR-212 expression was significantly correlated with poor prognostic features including positive lymph node metastasis and advanced tumor-node-metastasis (TNM) stage. Moreover, we demonstrated that miR-212 is a novel independent prognostic marker for predicting 5-year survival of NSCLC patients. The ectopic overexpression of miR-212 inhibited cell migration, invasion and EMT, while downregulated miR-212 reversed the effect. In addition, miR-212 regulated SOX4 by directly binding to its 3'-untranslated region (3'-UTR), leading to suppression of EMT progression. In clinical samples of NSCLC, miR-212 was negatively correlated with SOX4, which was upregulated in NSCLC. Alteration in SOX4 expression reversed the functional effects of miR-212 in regards to migration, invasion and EMT in the NSCLC cells. In conclusion, our data indicated that miR-212 functions as a tumor-suppressor gene by regulating EMT and metastasis of NSCLC by targeting SOX4 signaling, and may represent a novel potential therapeutic target and prognostic marker for NSCLC.

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