Disrupted mossy fiber connections from defective embryonic neurogenesis contribute to SOX11-associated schizophrenia.

Abnormal mossy fiber connections in the hippocampus have been implicated in schizophrenia. However, it remains unclear whether this abnormality in the patients is genetically determined and whether it contributes to the onset of schizophrenia. Here, we showed that iPSC-derived hippocampal NPCs from schizophrenia patients with the A/A allele at SNP rs16864067 exhibited abnormal NPC polarity, resulting from the downregulation of SOX11 by this high-risk allele. In the SOX11-deficient mouse brain, abnormal NPC polarity was also observed in the hippocampal dentate gyrus, and this abnormal NPC polarity led to defective hippocampal neurogenesis-specifically, irregular neuroblast distribution and disrupted granule cell morphology. As granule cell synapses, the mossy fiber pathway was disrupted, and this disruption was resistant to activity-induced mossy fiber remodeling in SOX11 mutant mice. Moreover, these mutant mice exhibited diminished PPI and schizophrenia-like behaviors. Activation of hippocampal neurogenesis in the embryonic brain, but not in the adult brain, partially alleviated disrupted mossy fiber connections and improved schizophrenia-related behaviors in mutant mice. We conclude that disrupted mossy fiber connections are genetically determined and strongly correlated with schizophrenia-like behaviors in SOX11-deficient mice. This disruption may reflect the pathological substrate of SOX11-associated schizophrenia.

SOX4-induced upregulation of ARHGAP9 promotes the progression of acute myeloid leukemia.

Acute myeloid leukemia (AML) is the most common acute leukemia. Rho GTPase activating protein 9 (ARHGAP9) has been reported to be positively correlated with overall survival of AML patients, but the specific molecular function remains unclear. This study aims to further explore the functional role and the molecular mechanism of ARHGAP9 in AML cells. The expression level of ARHGAP9 in AML cells was measured using quantitative real-time PCR (qRT-PCR) and western blot. Cell transfection was performed to interfere ARHGAP9. CCK-8, flow cytometry and TUNEL assays were conducted to detect cell viability, cell cycle distribution and apoptosis, respectively. The binding relationship between SOX4 and ARHGAP9 promoter was verified using luciferase reporter assay and chromatin immunoprecipitation. The results showed that ARHGAP9 was upregulated in AML cells. Interference of ARHGAP9 greatly reduced cell viability and induced cell cycle arrest in G1 phase, accompanied with the reduction of Ki67, PCNA, cyclin D1, cyclin E1, CDK4 and CDK6. In addition, Interference of ARHGAP9 greatly promoted cell apoptosis, accompanied with the decreased protein expression of Bcl-2 and the increased protein expression of Bax, cleaved caspase 3 and cleaved caspase 9. Furthermore, SOX4 directly bound to ARHGAP9 promoter and regulated ARHGAP9 expression. In conclusion, this study suggested that ARHGAP9 interference exerted an anti-tumor effect through inhibiting cell proliferation, blocking cell cycle progression, and promoting cell apoptosis in AML cells. ARHGAP9 may serve as a novel therapeutic target for AML.

XIST promotes cell proliferation and invasion by regulating miR-140-5p and SOX4 in retinoblastoma.

BACKGROUND: Retinoblastoma (RB) is the most common intraocular malignancy in children. Long non-coding RNA X-inactive specific transcript (lncRNA XIST) has been reported to be associated with RB, but research on the mechanism of XIST is not well studied. METHODS: Expressions of XIST, microRNA-140-5p (miR-140-5p), and sex-determining region Y-related high-mobility group box 4 (SOX4) were analyzed by qRT-PCR or Western blot. Relationships of XIST, SOX4, and miR-140-5p were evaluated by dual-luciferase reporter assay and Spearman's analysis. Cell Counting Kit-8 (CCK-8) and Transwell assay were performed to assess the function of XIST on RB cell proliferation and invasion. RESULTS: In RB tissues, XIST and SOX4 expressions were obviously increased, but the miR-140-5p expression was markedly reduced. XIST expression was positively related to SOX4 expression while negatively correlated with miR-140-5p expression, and negative correlation was exhibited between miR-140-5p and SOX4 expression in RB tissues. XIST was confirmed to directly bind to miR-140-5p, and SOX4 was one target of miR-140-5p. XIST knockdown could impede RB cell proliferation and invasion, while miR-140-5p inhibition reversed the effects. In addition, XIST overexpression or miR-140-5p inhibition could abrogate the inhibition of SOX4 silencing on cell proliferation and invasion of RB cells. CONCLUSIONS: XIST was obviously increased in RB tissues and cells, and XIST inhibition repressed the proliferation and invasion of RB cells by miR-140-5p/SOX4 axis, which may provide new understandings of the XIST molecular mechanism in RB.

Hierarchical control of interleukin 13 (IL-13) signals in lung fibroblasts by STAT6 and SOX11.

Interleukin (IL)-13 is a signature cytokine of type 2 inflammation important for the pathogenesis of various diseases, including allergic diseases. Signal transducer and activator of transcription (STAT) 6 is a critical transcriptional factor for the IL-13 signals; however, it remains unknown how expression of the IL-13-induced genes is differentiated by the transcriptional machineries. In this study, we identified IL-13-induced transcriptional factors in lung fibroblasts using DNA microarrays in which SOX11 was included. Knockdown of SOX11 down-regulated expression of periostin and CCL26, both of which are known to be downstream molecules of IL-13, whereas enforced expression of SOX11 together with IL-13 stimulation enhanced expression of periostin. Moreover, we found that in DNA microarrays combining IL-13 induction and SOX11 knockdown there exist both SOX11-dependent and -independent molecules in IL-13-inducible molecules. In the former, many inflammation-related and fibrosis-related molecules, including periostin and CCL26, are involved. These results suggest that SOX11 acts as a trans-acting transcriptional factor downstream of STAT6 and that in lung fibroblasts the IL-13 signals are hierarchically controlled by STAT6 and SOX11.

Sox4 Promotes Atoh1-Independent Intestinal Secretory Differentiation Toward Tuft and Enteroendocrine Fates.

BACKGROUND & AIMS: The intestinal epithelium is maintained by intestinal stem cells (ISCs), which produce postmitotic absorptive and secretory epithelial cells. Initial fate specification toward enteroendocrine, goblet, and Paneth cell lineages requires the transcription factor Atoh1, which regulates differentiation of the secretory cell lineage. However, less is known about the origin of tuft cells, which participate in type II immune responses to parasite infections and appear to differentiate independently of Atoh1. We investigated the role of Sox4 in ISC differentiation. METHODS: We performed experiments in mice with intestinal epithelial-specific disruption of Sox4 (Sox4fl/fl:vilCre; SOX4 conditional knockout [cKO]) and mice without disruption of Sox4 (control mice). Crypt- and single-cell-derived organoids were used in assays to measure proliferation and ISC potency. Lineage allocation and gene expression changes were studied by immunofluorescence, real-time quantitative polymerase chain reaction, and RNA-seq analyses. Intestinal organoids were incubated with the type 2 cytokine interleukin 13 and gene expression was analyzed. Mice were infected with the helminth Nippostrongylus brasiliensis and intestinal tissues were collected 7 days later for analysis. Intestinal tissues collected from mice that express green fluorescent protein regulated by the Atoh1 promoter (Atoh1GFP mice) and single-cell RNA-seq analysis were used to identify cells that coexpress Sox4 and Atoh1. We generated SOX4-inducible intestinal organoids derived from Atoh1fl/fl:vilCreER (ATOH1 inducible knockout) mice and assessed differentiation. RESULTS: Sox4cKO mice had impaired ISC function and secretory differentiation, resulting in decreased numbers of tuft and enteroendocrine cells. In control mice, numbers of SOX4+ cells increased significantly after helminth infection, coincident with tuft cell hyperplasia. Sox4 was activated by interleukin 13 in control organoids; SOX4cKO mice had impaired tuft cell hyperplasia and parasite clearance after infection with helminths. In single-cell RNA-seq analysis, Sox4+/Atoh1- cells were enriched for ISC, progenitor, and tuft cell genes; 12.5% of Sox4-expressing cells coexpressed Atoh1 and were enriched for enteroendocrine genes. In organoids, overexpression of Sox4 was sufficient to induce differentiation of tuft and enteroendocrine cells-even in the absence of Atoh1. CONCLUSIONS: We found Sox4 promoted tuft and enteroendocrine cell lineage allocation independently of Atoh1. These results challenge the longstanding model in which Atoh1 is the sole regulator of secretory differentiation in the intestine and are relevant for understanding epithelial responses to parasitic infection.

C. elegans SoxB genes are dispensable for embryonic neurogenesis but required for terminal differentiation of specific neuron types.

Neurogenesis involves deeply conserved patterning molecules, such as the proneural basic helix-loop-helix transcription factors. Sox proteins and specifically members of the SoxB and SoxC groups are another class of conserved transcription factors with an important role in neuronal fate commitment and differentiation in various species. In this study, we examine the expression of all five Sox genes of the nematode C. elegans and analyze the effect of null mutant alleles of all members of the SoxB and SoxC groups on nervous system development. Surprisingly, we find that, unlike in other systems, neither of the two C. elegans SoxB genes sox-2 (SoxB1) and sox-3 (SoxB2), nor the sole C. elegans SoxC gene sem-2, is broadly expressed throughout the embryonic or adult nervous system and that all three genes are mostly dispensable for embryonic neurogenesis. Instead, sox-2 is required to maintain the developmental potential of blast cells that are generated in the embryo but divide only postembryonically to give rise to differentiated neuronal cell types. Moreover, sox-2 and sox-3 have selective roles in the terminal differentiation of specific neuronal cell types. Our findings suggest that the common themes of SoxB gene function across phylogeny lie in specifying developmental potential and, later on, in selectively controlling terminal differentiation programs of specific neuron types, but not in broadly controlling neurogenesis.

SOX11 promotes invasive growth and ductal carcinoma in situ progression.

Here, we show that SOX11, an embryonic mammary marker that is normally silent in postnatal breast cells, is expressed in many oestrogen receptor-negative preinvasive ductal carcinoma in situ (DCIS) lesions. Mature mammary epithelial cells engineered to express SOX11 showed alterations in progenitor cell populations, including an expanded basal-like population with increased aldehyde dehydrogenase (ALDH) activity, and increased mammosphere-forming capacity. DCIS.com cells engineered to express SOX11 showed increased ALDH activity, which is a feature of cancer stem cells. The CD44+/CD24-/ALDH+ cell population was increased in DCIS.com cells that expressed SOX11. Upregulating SOX11 expression in DCIS.com cells led to increased invasive growth both in vitro and when they were injected intraductally in a mouse model of DCIS that recapitulates human disease. Invasive lesions formed sooner and tumour growth was augmented in vivo, suggesting that SOX11 contributes to the progression of DCIS to invasive breast cancer. We identified potential downstream effectors of SOX11 during both microinvasive and invasive tumour growth stages, including several with established links to regulation of progenitor cell function and prenatal developmental growth. Our findings suggest that SOX11 is a potential biomarker for DCIS lesions containing cells harbouring distinct biological features that are likely to progress to invasive breast cancer. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

SoxC transcription factors are essential for the development of the inner ear.

Hair cells, the mechanosensory receptors of the inner ear, underlie the senses of hearing and balance. Adult mammals cannot adequately replenish lost hair cells, whose loss often results in deafness or balance disorders. To determine the molecular basis of this deficiency, we investigated the development of a murine vestibular organ, the utricle. Here we show that two members of the SoxC family of transcription factors, Sox4 and Sox11, are down-regulated after the epoch of hair cell development. Conditional ablation of SoxC genes in vivo results in stunted sensory organs of the inner ear and loss of hair cells. Enhanced expression of SoxC genes in vitro conversely restores supporting cell proliferation and the production of new hair cells in adult sensory epithelia. These results imply that SoxC genes govern hair cell production and thus advance these genes as targets for the restoration of hearing and balance.

Sox11-modified mesenchymal stem cells (MSCs) accelerate bone fracture healing: Sox11 regulates differentiation and migration of MSCs.

Mesenchymal stem cells (MSCs) are a promising cell resource for tissue engineering. Sry-related high-mobility group box 11 (Sox11) plays critical roles in neural development and organogenesis. In the present study, we investigated the role of Sox11 in regulating trilineage differentiation (osteogenesis, adipogenesis, and chondrogenesis) and migration of MSCs, and explored the effect of systemically administrated Sox11-modified MSCs on bone fracture healing using the rat model of open femur fracture. Our results demonstrated that Sox11 overexpression increased the trilineage differentiation and migration of MSCs, as well as cell viability under oxidative stress. The effect of Sox11 on osteogenesis was confirmed by ectopic bone formation assay conducted in nude mice. In addition, we found that Sox11 could activate the bone morphogenetic protein (BMP)/Smad signaling pathway in MSCs. By dual-luciferase reporter assay, we also demonstrated that Sox11 could transcriptionally activate runt-related transcription factor 2 (Runx2) and CXC chemokine receptor-4 (CXCR4) expression. The activation of the BMP/Smad signaling pathway and Runx2, CXCR4 expression may have a synergic effect, which largely contributed to the effect of Sox11 on MSC fate determination and migration. Finally, using an open femur fracture model in rats, we found that a larger number of MSCs stably expressing Sox11 migrated to the fracture site and improved bone fracture healing. Taken together, our study shows that Sox11 is an important regulator of MSC differentiation and migration, and Sox11-modified MSCs may have clinical implication for accelerating bone fracture healing, which can reduce the delayed unions or nonunions.

SOX11 regulates PAX5 expression and blocks terminal B-cell differentiation in aggressive mantle cell lymphoma.

Mantle cell lymphoma (MCL) is one of the most aggressive lymphoid neoplasms whose pathogenesis is not fully understood. The neural transcription factor SOX11 is overexpressed in most MCL but is not detected in other mature B-cell lymphomas or normal lymphoid cells. The specific expression of SOX11 in MCL suggests that it may be an important element in the development of this tumor, but its potential function is not known. Here, we show that SOX11 promotes tumor growth in a MCL-xenotransplant mouse model. Using chromatin immunoprecipitation microarray analysis combined with gene expression profiling upon SOX11 knockdown, we identify target genes and transcriptional programs regulated by SOX11 including the block of mature B-cell differentiation, modulation of cell cycle, apoptosis, and stem cell development. PAX5 emerges as one of the major SOX11 direct targets. SOX11 silencing downregulates PAX5, induces BLIMP1 expression, and promotes the shift from a mature B cell into the initial plasmacytic differentiation phenotype in both primary tumor cells and an in vitro model. Our results suggest that SOX11 contributes to tumor development by altering the terminal B-cell differentiation program of MCL and provide perspectives that may have clinical implications in the diagnosis and design of new therapeutic strategies.

SOX4 enables oncogenic survival signals in acute lymphoblastic leukemia.

The Sox4 transcription factor mediates early B-cell differentiation. Compared with normal pre-B cells, SOX4 promoter regions in Ph(+) ALL cells are significantly hypomethylated. Loss and gain-of-function experiments identified Sox4 as a critical activator of PI3K/AKT and MAPK signaling in ALL cells. ChIP experiments confirmed that SOX4 binds to and transcriptionally activates promoters of multiple components within the PI3K/AKT and MAPK signaling pathways. Cre-mediated deletion of Sox4 had little effect on normal pre-B cells but compromised proliferation and viability of leukemia cells, which was rescued by BCL2L1 and constitutively active AKT and p110 PI3K. Consistent with these findings, high levels of SOX4 expression in ALL cells at the time of diagnosis predicted poor outcome in a pediatric clinical trial (COG P9906). Collectively, these studies identify SOX4 as a central mediator of oncogenic PI3K/AKT and MAPK signaling in ALL.

Sox4 up-regulates Cyr61 expression in colon cancer cells.

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

The C. elegans SoxC protein SEM-2 opposes differentiation factors to promote a proliferative blast cell fate in the postembryonic mesoderm.

The proper development of multicellular organisms requires precise regulation and coordination of cell fate specification, cell proliferation and differentiation. Abnormal regulation and coordination of these processes could lead to disease, including cancer. We have examined the function of the sole C. elegans SoxC protein, SEM-2, in the M lineage, which produces the postembryonic mesoderm. We found that SEM-2/SoxC is both necessary and sufficient to promote a proliferating blast cell fate, the sex myoblast fate, over a differentiated striated bodywall muscle fate. A number of factors control the specific expression of sem-2 in the sex myoblast precursors and their descendants. This includes direct control of sem-2 expression by a Hox-PBC complex. The crucial nature of the HOX/PBC factors in directly enhancing expression of this proliferative factor in the C. elegans M lineage suggests a possible more general link between Hox-PBC factors and SoxC proteins in regulating cell proliferation.

Transcription factor Sox11 is essential for both embryonic and adult neurogenesis.

BACKGROUND: Neurogenesis requires neural progenitor cell (NPC) proliferation, neuronal migration, and differentiation. During embryonic development, neurons are generated in specific areas of the developing neuroepithelium and migrate to their appropriate positions. In the adult brain, neurogenesis continues in the subgranular zone (SGZ) of the hippocampal dentate gyrus and the subventricular zone (SVZ) of the lateral ventricle. Although neurogenesis is fundamental to brain development and function, our understanding of the molecular mechanisms that regulate neurogenesis is still limited. RESULTS: In this study, we generated a Sox11 floxed allele and a Sox11 null allele in mice using the Cre-loxP technology. We first analyzed the role of the transcription factor Sox11 in embryonic neurogenesis using Sox11 null embryos. We also examined the role of Sox11 in adult hippocampal neurogenesis using Sox11 conditional knockout mice in which Sox11 is specifically deleted in adult NPCs. Sox11 null embryos developed small and disorganized brains, accompanied by transient proliferation deficits in NPCs. Deletion of Sox11 in adult NPCs blunted proliferation in the SGZ. Using functional genomics, we identified potential downstream target genes of Sox11. CONCLUSIONS: Taken together, our work provides evidence that Sox11 is required for both embryonic and adult neurogenesis, and identifies potential downstream target genes.

[Expression of SOX11 transcription factor. Its implication in mantle cell lymphoma]. / Expresión del factor de transcripción SOX11. Su implicancia en el linfoma de células del manto.

SOX11, belonging to the family of genes SOXC, is a transcript factor involved in the embryonic neurogenesis and tissue remodeling, also participating in the control of cell proliferation. Its role in lymphomagenesis still remains unknown. Recent studies have shown aberrant SOX11 nuclear protein expression as well as mRNA levels in patients with mantle cell lymphoma (MCL). Although the majority of these lymphomas have an aggressive clinical course, there is a subgroup of patients with an indolent clinical evolution, suggesting a greater heterogeneity of this disease. Currently, there are contradictions regarding the association of SOX11 gene expression and outcome in MCL, while some authors have related the lack of SOX11 expression with good prognosis, others find it associated with an adverse clinical course. This difference in the gene expression could be associated to epigenetic mechanisms such as modifications at the histone level and DNA methylation that would allow the aberrant expression of this gene in some lymphoid neoplasias, including LCM. More knowledge of gene SOX11 in LCM will lead to a greater understanding of those mechanisms involved in the pathogenesis and progression of this lymphoma, also the involvement of SOX11 in these processes.

SoxC transcription factors are required for neuronal differentiation in adult hippocampal neurogenesis.

Neural stem cells (NSCs) generate new hippocampal dentate granule neurons throughout adulthood. The genetic programs controlling neuronal differentiation of adult NSCs are only poorly understood. Here we show that, in the adult mouse hippocampus, expression of the SoxC transcription factors Sox4 and Sox11 is initiated around the time of neuronal commitment of adult NSCs and is maintained in immature neurons. Overexpression of Sox4 and Sox11 strongly promotes in vitro neurogenesis from adult NSCs, whereas ablation of Sox4/Sox11 prevents in vitro and in vivo neurogenesis from adult NSCs. Moreover, we demonstrate that SoxC transcription factors target the promoters of genes that are induced on neuronal differentiation of adult NSCs. Finally, we show that reprogramming of astroglia into neurons is dependent on the presence of SoxC factors. These data identify SoxC proteins as essential contributors to the genetic network controlling neuronal differentiation in adult neurogenesis and neuronal reprogramming of somatic cells.

SOX11 contributes to the regulation of GDF5 in joint maintenance.

BACKGROUND: Individual skeletal elements of the vertebrate limbs arise through a segmentation process introducing joints in specific locations. However, the molecular pathways controlling joint formation and subsequent joint maintenance are largely unknown. In this study, we focused on SOX11, and its contribution to the regulation of GDF5, a secreted signal necessary for proper joint formation and postnatal joint homeostasis. RESULTS: Sox11 is initially expressed broadly in the murine cartilage condensations at early stages of skeletal development, but its expression is specifically increased in the forming joint interzone as is forms. SOX11 overexpression can directly activate GDF5 expression both in vitro and in micromass cell cultures prepared from chick limb buds. Conserved SOX family binding sites are present in the 5' UTR region of the GDF5 gene and we show SOX11 can specifically bind to one of them. While misexpression of Sox11 in developing chick limbs through RCAS virus infection does not induce Gdf5 expression in ectopic locations, it does enhance its expression. To explore the roles of Sox11 in joint homeostasis, we analyzed adult knee joints in an osteoarthritis mouse model where the medial meniscus and the medial collateral ligament were removed. We also analyzed knee joints from human subjects who underwent total knee replacement surgery. We find that SOX11 is mainly expressed in the weight-bearing areas of knee joints, and its expression is decreased in degraded cartilage during progression of knee osteoarthritis in both mice and humans. CONCLUSIONS: This work implicates SOX11 as a potential regulator of GDF5 expression in joint maintenance and suggests a possible role in the pathogenesis of osteoarthritis.

Sox4, EMT programs, and the metastatic progression of breast cancers: mastering the masters of EMT.

Epithelial-mesenchymal transition (EMT) programs require the expression of a variety of so-called master regulators of EMT, including members of the Snail, Zeb, and Twist transcription factor families. Teleologically, the requirement for such a diverse group of 'master regulators' seems evolutionarily cumbersome, and emerging evidence indicates that these transcription factors do in fact mediate unique and specialized functions, suggesting the existence of higher-order 'masters' that truly direct and coordinate EMT programs. Accordingly, Tiwari and colleagues recently delineated an elegant pathway wherein transforming growth factor-beta stimulates Sox4 expression, which induces that of the histone methyltransferase, Ezh2, thereby reprogramming the epigenome to elicit EMT programs and metastasis of breast cancers. This viewpoint highlights Sox4 as a 'new' master of EMT programs and metastatic breast cancer.

Embryonic mammary signature subsets are activated in Brca1-/- and basal-like breast cancers.

INTRODUCTION: Cancer is often suggested to result from development gone awry. Links between normal embryonic development and cancer biology have been postulated, but no defined genetic basis has been established. We recently published the first transcriptomic analysis of embryonic mammary cell populations. Embryonic mammary epithelial cells are an immature progenitor cell population, lacking differentiation markers, which is reflected in their very distinct genetic profiles when compared with those of their postnatal descendents. METHODS: We defined an embryonic mammary epithelial signature that incorporates the most highly expressed genes from embryonic mammary epithelium when compared with the postnatal mammary epithelial cells. We looked for activation of the embryonic mammary epithelial signature in mouse mammary tumors that formed in mice in which Brca1 had been conditionally deleted from the mammary epithelium and in human breast cancers to determine whether any genetic links exist between embryonic mammary cells and breast cancers. RESULTS: Small subsets of the embryonic mammary epithelial signature were consistently activated in mouse Brca1-/- tumors and human basal-like breast cancers, which encoded predominantly transcriptional regulators, cell-cycle, and actin cytoskeleton components. Other embryonic gene subsets were found activated in non-basal-like tumor subtypes and repressed in basal-like tumors, including regulators of neuronal differentiation, transcription, and cell biosynthesis. Several embryonic genes showed significant upregulation in estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and/or grade 3 breast cancers. Among them, the transcription factor, SOX11, a progenitor cell and lineage regulator of nonmammary cell types, is found highly expressed in some Brca1-/- mammary tumors. By using RNA interference to silence SOX11 expression in breast cancer cells, we found evidence that SOX11 regulates breast cancer cell proliferation and cell survival. CONCLUSIONS: Specific subsets of embryonic mammary genes, rather than the entire embryonic development transcriptomic program, are activated in tumorigenesis. Genes involved in embryonic mammary development are consistently upregulated in some breast cancers and warrant further investigation, potentially in drug-discovery research endeavors.

MicroRNA-138 suppresses ovarian cancer cell invasion and metastasis by targeting SOX4 and HIF-1α.

Metastasis is the major factor affecting patient survival in ovarian cancer. However, its molecular mechanisms remain unclear. Our study used isogenic pairs of low- and high-invasive ovarian cancer cell lines to demonstrate the downregulation of miRNA-138 in the highly invasive cells, and its functioning as an inhibitor of cell migration and invasion. An orthotopic xenograft mouse model further demonstrated that the expression of miRNA-138 inhibited ovarian cancer metastasis to other organs. Results indicated that miR-138 directly targeted SRY-related high mobility group box 4 (SOX4) and hypoxia-inducible factor-1α (HIF-1α), and overexpression of SOX4 and HIF-1α effectively reversed the miR-138-mediated suppression of cell invasion. Epidermal growth factor receptor acted as the downstream molecule of SOX4 by way of direct transcriptional control, whereas Slug was the downstream molecule of HIF-1α by way of proteasome-mediated degradation. Analysis of human ovarian tumors further revealed downregulation of miR-138 and upregulation of SOX4 in late-stage tumors. Patients with miR-138(low)/SOX(high) signature are predominant in late stage and tend to have malignant phenotypes including lymph nodes metastasis, larger ascites volume and higher tumor grade. Our study demonstrates the role and clinical relevance of miR-138 in ovarian cancer cell invasion and metastasis, providing a potential therapeutic strategy for suppression of ovarian cancer metastasis by targeting SOX4 and HIF-1α pathways.