UNASSIGNED: The transcription factor, SOX13 is part of the SOX family. SOX proteins are crucial in the progression of many cancers, and some correlate with carcinogenesis. Nonetheless, the biological and clinical implications of SOX13 in human breast cancer (BC) remain rarely known.
UNASSIGNED: We evaluated the survival and expression data of SOX13 in BC patients via the UNLCAL, GEPIA, TIMER, and Kaplan-Meier plotter databases. Immunohistochemistry (IHC) was used to verify clinical specimens. The gene alteration rates of SOX13 were acquired on the online web cBioportal. With the aid of the TCGA data, the association between SOX13 mRNA expression and copy number alterations (CNA) and methylation was determined. LinkedOmics was used to identify the genes that co-expressed with SOX13 and the regulators. Immune infiltration and tumor microenvironment evaluations were assessed by ImmuCellAI and TIMER2.0 databases. SOX13 correlated drug resistance analysis was performed using the GDSC2 database.
UNASSIGNED: Higher SOX13 expression was discovered in BC tissues in comparison to normal tissues. Moreover, increased gene mutation and amplification of SOX13 were found in BC. Patients with increased SOX13 expression levels showed worse overall survival (OS). Cox analysis showed that SOX13 independently served as a prognostic indicator for poor survival in BC. Further, the expression of SOX13 was also confirmed to be correlated with tumor microenvironment and diverse infiltration of immune cells. In terms of drug sensitivity analysis, we found higher expression level of SOX13 predicts a high IC50 value for most of 198 drugs which predicts drug resistance.
UNASSIGNED: The present findings demonstrated that high expression of SOX13 negatively relates to prognosis and SOX13 plays an important role in cancer immunity. Therefore, SOX13 may potentially be adopted as a biomarker for predicting BC prognosis and infiltration of immune cells.

Cigarette smoke initiates an inflammatory response that has aftermath long after quitting. We segregated former smokers, according to their lung function and their co-founding diseases, in 3 groups: Cancer, Emphysema and COPD. Then we searched for outlier genes in intersections of Venn diagrams where we identified 6 subsets and 23 genes that may be responsible for disease outcome. Genes expressed in the cancer patients with or without emphysema (PPA subset) were BHLH, FPRL2, CD49D, DEADH, NRs4A3, MBLL, GNS, BE675435, ISGF-3, and FLJ23462. Patients with emphysema as co-founding disease, with or without cancer (APP), had only ANXA2 in common. Genes expressed only in non-cancer patients (AAP subset) of COPD group were IL-1A, SOX13, RPP38; TBXA2R, NPEPL1, CFLAR, TFEB, PRKCBP1, IGF1R, DDX11, and KCNAB1. HIV-1Rev was the gene expressed in cancer patients with emphysema (APA subset). Then, we also looked at out-layers genes significantly expressed in all patients (PPP subset with 5066 genes), the down-regulated in Emphysema were MMP9, PLUNC, CEACAM5, and NR4A1 while the up-regulated were F2R, COL15A1, PDE4C, and BGN. We chose genes and checked them at the protein level on immune cells, this showed that neutrophils from Cancer group had increased expression of CD49d, and their total number was also increased in bronchial-alveolar lavage (154%). Macrophages in the lung of patients with emphysema were associated with a significant increase of adhesion molecule CD58 and to significant CD95 decrease, indicating they do not die. Besides, macrophages downregulated MMP9 in the lung compared to blood macrophages. Overall, we find that cancer progression requires a stickier and greater number of neutrophils in the lung while emphysema requires stickier and longevous macrophages to lead matrix destruction, and together with higher expression of SOX13 and RPP38, may promote autoimmunity. We also identified two genes, ANXA2 and HIV1-rev, that may be a pivot between cancer and emphysema outcome of inflammation.

Atherosclerosis is a chronic inflammatory disease and occurs preferentially in arterial regions exposed to disturbed blood flow (d-flow) while the stable flow (s-flow) regions are spared. D-flow induces endothelial inflammation and atherosclerosis by regulating endothelial gene expression partly through the flow-sensitive transcription factors (FSTFs). Most FSTFs, including the well-known Kruppel-like factors KLF2 and KLF4, have been identified from in vitro studies using cultured endothelial cells (ECs). Since many flow-sensitive genes and pathways are lost or dysregulated in ECs during culture, we hypothesized that many important FSTFs in ECs in vivo have not been identified. We tested the hypothesis by analyzing our recent gene array and single-cell RNA sequencing (scRNAseq) and chromatin accessibility sequencing (scATACseq) datasets generated using the mouse partial carotid ligation model. From the analyses, we identified 30 FSTFs, including the expected KLF2/4 and novel FSTFs. They were further validated in mouse arteries in vivo and cultured human aortic ECs (HAECs). These results revealed 8 FSTFs, SOX4, SOX13, SIX2, ZBTB46, CEBPβ, NFIL3, KLF2, and KLF4, that are conserved in mice and humans in vivo and in vitro. We selected SOX13 for further studies because of its robust flow-sensitive regulation, preferential expression in ECs, and unknown flow-dependent function. We found that siRNA-mediated knockdown of SOX13 increased endothelial inflammatory responses even under the unidirectional laminar shear stress (ULS, mimicking s-flow) condition. To understand the underlying mechanisms, we conducted an RNAseq study in HAECs treated with SOX13 siRNA under shear conditions (ULS vs. oscillatory shear mimicking d-flow). We found 94 downregulated and 40 upregulated genes that changed in a shear- and SOX13-dependent manner. Several cytokines, including CXCL10 and CCL5, were the most strongly upregulated genes in HAECs treated with SOX13 siRNA. The robust induction of CXCL10 and CCL5 was further validated by qPCR and ELISA in HAECs. Moreover, the treatment of HAECs with Met-CCL5, a specific CCL5 receptor antagonist, prevented the endothelial inflammation responses induced by siSOX13. In addition, SOX13 overexpression prevented the endothelial inflammation responses. In summary, SOX13 is a novel conserved FSTF, which represses the expression of pro-inflammatory chemokines in ECs under s-flow. Reduction of endothelial SOX13 triggers chemokine expression and inflammatory responses, a major proatherogenic pathway.

Sex-determining region Y (SRY)-related high mobility group (HMG) box (SOX) proteins are pivotal transcriptional factors that play essential roles in embryonic development, cell fate decisions and cancer development. The molecular mechanism of SOX13, a member of the SOX family, in hepatocellular carcinoma (HCC) remains largely unknown. In the current study, we found that HCC cells were able to form spheroids in serum-free suspension culture and that SOX13 expression was upregulated in spheroids enriched for cancer stem cells (CSCs). Inhibition of SOX13 in HCC-LM3 and MHCC-97H cells decreased the expression of stemness-related genes; attenuated spheroid formation, anchor-dependent and anchor-independent cell proliferation and tumorigenicity; and enhanced sensitivity to drug treatment. Furthermore, based on analysis of TCGA dataset, the results indicated that SOX13 expression was obviously upregulated and closely associated with poor prognosis in HCC patients. Moreover, SOX13 was correlated with TAZ and CD24 expression. These data strongly demonstrated that SOX13 is involved in maintaining cancer stem-like properties in HCC cells and plays a critical role in HCC development.

BACKGROUND: Long non-coding RNAs (lncRNAs) play crucial roles in the regulation and treatment of multiple myeloma (MM). The objective of this research was to study the functional mechanism of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in MM.
METHODS: MALAT1, microRNA-1271-5p (miR-1271-5p), and SRY-Box 13 (SOX13) levels were examined by quantitative real-time polymerase chain reaction (qRT-PCR). Cell viability, apoptosis, and invasion were respectively assayed using 3-(4, 5-dimethylthiazol-2-y1)-2, 5-diphenyl tetrazolium bromide (MTT), flow cytometry, and transwell assay. Glycolysis was evaluated by glucose consumption, lactate production, ATP/ADP ratio, and the detection of related enzymes. Associated proteins were measured using Western blot. Target relation was verified via dual-luciferase reporter assay. Xenograft tumor assay was implemented to study the influence of MALAT1 on MM in vivo.
RESULTS: The up-regulation of MALAT1 and the down-regulation of miR-1271-5p were found in MM serums and cells. MALAT1 knockdown suppressed cell viability, invasion, and glycolysis while expedited cell apoptosis in MM cells. MALAT1 directly targeted miR-1271-5p and miR-1271-5p depression reverted the effects of MALAT1 knockdown on MM cells. SOX13 was a target of miR-1271-5p and SOX13 overexpression weakened the effects of miR-1271-5p on MM. MALAT1 indirectly modulated SOX13 expression through targeting miR-1271-5p. MALAT1 down-regulation inhibited MM growth by miR-1271-5p/SOX13 axis in vivo.
CONCLUSIONS: LncRNA MALAT1 expedited MM tumorigenesis, invasion, and glycolysis via miR-1271-5p/SOX13 axis. MALAT1 might contribute to the therapy of MM as a promising indicator.

Aberrant expression of forkhead box C1 (FOXC1) promotes tumor metastasis in multiple human malignant tumors. However, the upstream modulating mode and downstream molecular mechanism of FOXC1 in metastasis of colorectal cancer (CRC) remain unclear. Herein we describe a systematic analysis of FOXC1 expression and prognosis in CRC performed on our clinical data and public databases, which indicated that FOXC1 upregulation in CRC samples was significantly associated with poor prognosis. FOXC1 knockdown inhibited migration and invasion, whereas FOXC1 overexpression caused the opposite phenotype in vitro and in vivo. Furthermore, MMP10, SOX4 and SOX13 were verified as the target genes of FOXC1 for promoting CRC metastasis. MMP10 was demonstrated as the direct target and mediator of FOXC1. Interestingly, Ser241 and Ser272 of FOXC1 were identified as the key sites to interact with p38 and phosphorylation, which were critically required for maintaining the stability of FOXC1 protein. Moreover, FOXC1 was dephosphorylated by protein phosphatase 2A and phosphorylated by p38, which maintained FOXC1 protein stability through inhibiting ubiquitination. Expression of p38 was correlated with FOXC1 and MMP10 expression, indirectly indicating that FOXC1 was regulated by p38 MAPK. Therefore, FOXC1 is strongly suggested as a pro-metastatic gene in CRC by transcriptionally activating MMP10, SOX4 and SOX13; p38 interacts with and phosphorylates the Ser241 and ser272 sites of FOXC1 to maintain its stability by inhibiting ubiquitination and degradation. In conclusion, the protein stability of FOXC1 mediated by p38 contributes to the metastatic effect in CRC. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The SRY-related high-mobility-group box (Sox) gene family encodes a set of transcription factors and is defined by the presence of highly conserved domains. The Sox gene can be divided into 10 groups (A-J). The SoxD subpopulation consists of Sox5, Sox6, Sox13 and Sox23, which are involved in the transcriptional regulation of developmental processes, including embryonic development, nerve growth and cartilage formation. Recently, the SoxD gene family was recognized as important transcriptional regulators associated with many types of cancer. In addition, Sox5 and Sox6 are representatives of the D subfamily, and there are many related studies; however, there are few reports on Sox13 and Sox23. In this review, we first introduce the structures of the SoxD genes. Next, we summarize the latest research progress on SoxD in various types of cancer. Finally, we discuss the potential direction of future SoxD research. In general, the information reviewed here may contribute to future experimental design and increase the potential of SoxD as a cancer treatment target.

PAX8 is identified as a regulator in the pathogenesis of human tumours and an indicator of the prognosis for patients. However, the role of PAX8 on proliferation in gastric cancer have not been studied. This study was aimed to explore the expression pattern of PAX8 in gastric cancer, and investigate the effect of PAX8 on the proliferation of gastric cancer cells. PAX8 and SOX13 were identified to be synchronously up-regulated in primary gastric cancer in human gastric cancer tissues and the gastric cancer datasets of TCGA, and gastric cancer patients of combined high PAX8 and SOX13 expression showed poor prognosis. Furthermore, SOX13 can mediate PAX8 and its targeted genes, Aurora B and Cyclin B1, expression in AGS and MGC803 cell lines. Flow cytometry and EdU incorporation assays showed that silencing PAX8 can block the cell cycle of gastric cancer cell in G1 phase and SOX13 expression can rescue the arrested proliferative process induced by PAX8 silenced in CCK8 and colony formation assays. Thus, combined SOX13 and PAX8 expression regulate the proliferation of gastric cancer cells, and both SOX13 and PAX8 play an oncogene function in gastric cancer.

BACKGROUND: Angiogenesis plays a critical role in the progression of glioma. Previous studies have indicated that RNA-binding proteins (RBPs) interact with RNAs and participate in the regulation of the malignant behaviors of tumors. As a type of endogenous non-coding RNAs, circular RNAs (circRNAs) are abnormally expressed in various cancers and are involved in diverse tumorigeneses including angiogenesis.
METHODS: The expression levels of FUS, circ_002136, miR-138-5p, SOX13, and SPON2 were determined using quantitative real-time PCR (qRT-PCR) and western blot. Transient cell transfection was performed using the Lipofectamine 3000 reagent. The RNA-binding protein immunoprecipitation (RNA-IP) and the RNA pull-down assays were used to detect the interaction between FUS and circ_002136. The dual-luciferase reporter assay system was performed to detect the binding sites of circ_002136 and miR-138-5p, miR-138-5p and SOX13. The chromatin immunoprecipitation (ChIP) assays were used to examine the interactions between transcription factor SOX13 and its target proteins .
RESULTS: We demonstrated that down-regulation of FUS or circ_002136 dramatically inhibited the viability, migration and tube formation of U87 glioma-exposed endothelial cells (GECs). MiR-138-5p was down-regulated in GECs and circ_002136 functionally targeted miR-138-5p in an RNA-induced silencing complex (RISC). Inhibition of circ_002136, combined with the restoration of miR-138-5p, robustly reduced the angiogenesis of GECs. As a target gene of miR-138-5p, SOX13 was overexpressed in GECs and was proved to be involved in circ_002136 and miR-138-5p-mediated angiogenesis in gliomas. In addition, we found that SOX13 was directly associated with and activated the SPON2 promoter, thereby up-regulating the expression of SPON2 at the transcriptional level. Knockdown of SPON2 suppressed the angiogenesis in GECs. More important, SOX13 activated the FUS promoter and increased its expression, forming a feedback loop.
CONCLUSIONS: Our data suggests that the feedback loop of FUS/circ_002136/miR-138-5p/SOX13 played a crucial role in the regulation of angiogenesis in glioma. This also provides a potential target and an alternative strategy for combined glioma therapy.

Sox13, a group D member of the Sry-related high-mobility group box (Sox) transcription factor family, is expressed in various tissues including the hair follicle. However, its spatiotemporal expression patterns in the hair follicle and its role in hair development remain to be elucidated. To address these questions, we generated Sox13-LacZ-knock-in mice (Sox13LacZ/+), in which the LacZ reporter gene was inserted in-frame into exon 2, which contains the translation initiation codon. X-gal staining in Sox13LacZ/+ embryos revealed that Sox13 is initially expressed in the epithelial portion of the placode, and subsequently in the hair germ and the hair peg during early hair follicle development. In postnatal catagen and anagen, Sox13 was detected in the epithelial sheath, whereas in telogen, Sox13 was localized in the bulge region, where hair follicle stem cells reside. Immunohistochemistry with an anti-β-galactosidase antibody and anti-hair keratin antibodies that specifically mark the different layers of the hair follicle revealed that Sox13 was predominantly expressed in the outer root sheath in anagen. However, the integumentary structures of Sox13LacZ/LacZ mice were grossly and histologically indistinguishable from those of wild type mice. These results suggest that although Sox13 is dispensable for epidermal and adnexal development, Sox13 is a useful marker for early hair follicle development.