Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q86TM3 (cage)
 29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Campomelic dysplasia (CD; OMIM #114290) is an autosomal dominant, frequently lethal dysplasia syndrome whose primary features include angular bowing and shortening of the limbs, and sex reversal in the majority of affected XY individuals. Most CD cases have heterozygous de novo mutations in the coding region of the transcription factor gene SOX9 (SRY-related high-mobility group [HMG] box 9) in chromosome 17q. Here, we report a novel mutation of SOX9 in a female neonate with CD with autosomal sex reversal. Respiratory distress and cyanosis were noted at birth, and endotracheal intubation with mechanical ventilation was performed due to respiratory failure. The presenting phenotypes included dysmorphic face with macrocephaly, prominent forehead, low nasal bridge, cleft palate and micrognathia. Skeletal deformities characteristic of CD were observed, including narrow thoracic cage, hypoplastic scapulae, scoliosis and short limbs with anterolateral femoral and tibial bowing. The karyotype was 46,XY despite female external genitalia. SOX9 gene analysis revealed frameshift mutation (at nucleotide position 1095G-->AT) in the open reading frame, resulting in a frameshift with 211 new amino acids.
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PMID:Novel SOX9 gene mutation in campomelic dysplasia with autosomal sex reversal. 1718 44

Campomelic dysplasia (CD; OMIM #114290), a rare form of congenital short-limbed dwarfism, is due to mutations in SOX9, a member of the SOX (SRY-related HMG box) gene family. Multiparous mother at 38 weeks' gestation delivered a 3,272 g baby boy with characteristic phenotypes including bowing of the lower limbs, a narrow thoracic cage, 11 pairs of ribs, hypoplastic scapulae, macrocephaly, flattened supraorbital ridges and nasal bridge, cleft palate, and micrognathia. He underwent a tracheostomy at the age of three months for severe laryngomalacia after a number of repeated hospitalizations due to respiratory problems and died at the age of four months from progressive respiratory failure. He was diagnosed as having CD based on a novel frameshift mutation (p.Gln458ArgfsX12) in the SOX9 gene, the mutation which has not yet been reported in Korea.
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PMID:A case of campomelic dysplasia without sex reversal. 2121 44

MicroRNA-874 (miR-874), a novel cancer-associated microRNA (miRNA), has been reported to play a suppressive role in multiple malignancies. However, its function in cell migration and invasion in hepatocellular carcinoma (HCC) and the mechanisms responsible remain unclear. Here, we found miR-874 to be significantly downregulated in HCC tissues and cell lines. Moreover, this decreased expression strongly correlated with clinical stage and lymph node metastasis. Accordingly, ectopic expression of miR-874 in HCC cells markedly inhibited their migration, invasion, and epithelial-mesenchymal transition (EMT). Concerning the underlying mechanism, SRY (sex-determining region Y) -box 12 (SOX12) was identified as a direct target of miR-874, and its expression was found to be inversely correlated with that of this miRNA in HCC cells. Importantly, SOX12 knockdown had an inhibitory effect on HCC cells similar to that caused by miR-874 overexpression, whereas SOX12 overexpression in these cells negated the suppressive effects of miR-874 on migration, invasion, and EMT. Overall, these findings demonstrate that miR-874 inhibits metastasis and EMT in HCC by targeting SOX12, suggesting that this miRNA may constitute a promising therapeutic target for this disease.
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PMID:MiR-874 inhibits metastasis and epithelial-mesenchymal transition in hepatocellular carcinoma by targeting SOX12. 2867 Apr 93

Deregulated Hippo pathway signaling is associated with aberrant activation of the downstream effector yes-associated protein (YAP), an emerging key oncogenic mediator in cholangiocarcinoma (CCA). In our prior work, we have demonstrated that biliary transduction of YAP along with Akt as a permissive factor induces CCA in mice. To further delineate the mechanisms associated with YAP-associated biliary oncogenesis, we have established seven malignant murine cell lines from our YAP-driven murine CCA model. These cells express the CCA markers SRY (Sex Determining Region Y)-Box 9 (SOX9), cytokeratin (CK)-7 and 19 but lack hepatocyte nuclear factor 4 alpha and alpha-smooth muscle actin, markers of hepatocellular carcinoma and cancer-associated fibroblasts, respectively. Notably, the murine CCA cells can be readily implanted into mouse livers with resultant orthotopic tumor formation. In this unique syngeneic orthotopic murine model, tumors exhibit histopathologic features resembling human CCA. We analyzed transcriptome data from YAP-associated parent CCA tumor nodules and identified a gene expression pattern associated with chromosomal instability, known as CIN25. Similarly, mate-pair sequencing of the murine CCA cells revealed chromosomal missegregation with gains and losses of several whole chromosomes demonstrating aneuploidy. Of the CIN25 genes, forkhead box M1 (Foxm1), a key cell cycle regulator, was the most significantly upregulated CIN25 gene product. Accordingly, small interfering RNA (siRNA)-mediated silencing of YAP as well as FOXM1 inhibition with thiostrepton induced CCA cell death. These preclinical data imply a role for YAP-mediated chromosomal instability in cholangiocarcinoma, and suggest FOXM1 inhibition as a therapeutic target for CCA.
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PMID:YAP-associated chromosomal instability and cholangiocarcinoma in mice. 2946 42

Colorectal cancer (CRC) is the third most prevalent cancer and the fourth most common cause of cancer-associated mortality in males and females globally. Aberrant expression of microRNA-539 (miR-539) has been reported in multiple types of cancer. However, miR-539 expression, function and underlying mechanisms have not been clearly elucidated in CRC. In the present study, miR-539 expression was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in CRC tissues and cell lines. The effects of miR-539 on CRC cells were further examined in in vitro studies. In addition, the direct targets of miR-539 in CRC were investigated using bioinformatics, luciferase reporter assays, RT-qPCR and western blotting. miR-539 was revealed to be significantly downregulated in CRC cell lines and tissues. Decreased miR-539 expression was associated with lymph node metastasis and tumor-node-metastasis stage in patients with CRC. Functional assays revealed that the rescue of miR-539 expression attenuated CRC cell proliferation and invasion in vitro. Additionally, SRY-box 4 (SOX4) was validated as a direct target gene of miR-539 in CRC. Furthermore, SOX4 was revealed to be upregulated in CRC tissues at the mRNA and protein level. A significant negative correlation between miR-539 and SOX4 mRNA expression levels was observed in CRC tissues. Furthermore, upregulation of SOX4 partially restored the tumor suppressive effects of miR-539 on CRC cell proliferation and invasion. Taken together, this suggests that miR-539 may serve tumor-suppressive functions in CRC during the process of malignant transformation, by directly targeting SOX4. miR-539/SOX4-based targeted therapy may represent a potential novel treatment for patients with CRC.
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PMID:MicroRNA-539 inhibits colorectal cancer progression by directly targeting SOX4. 3001 65

Non-small-cell lung cancer (NSCLC) is the most common cause of cancer-associated mortality worldwide. MicroRNAs (miRs) are a class of small non-coding RNAs that are commonly dysregulated in human cancer. The aim of the current study was to evaluate the effect of miR-296-3p on the cell migration and invasion of NSCLC. Pairs of tumor tissues and para-cancerous tissues (n=50) were collected from patients with NSCLC, and the expression of miR-296-3p was analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Additionally, tumor cell viability, migration and invasion were examined in vitro using Cell Counting Kit-8, wound healing and Matrigel assays, respectively. Furthermore, potential targets of miR-296-3p were screened for using TargetScan and validated using a dual-luciferase reporter assay. The expression levels of phosphoinositide-3-kinase (PI3K), AKT serine/threonine kinase (AKT), mammalian target of rapamycin (mTOR), matrix metallopeptidase 2 (MMP2) and SRY-box 4 (SOX4) were detected by RT-qPCR and western blot analysis. The data indicated that miR-296-3p was downregulated in tumor tissues compared with adjacent normal tissues. Overexpression of miR-296-3p inhibited NSCLC cell viability, migration and invasion in vitro. Furthermore, apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1) was identified as a direct target of miR-296-3p. APEX1 expression was upregulated in tumor tissues compared with para-cancerous tissues, and the mRNA and protein expression levels of APEX1 were decreased following transfection of NSCLC cells with miR-296-3p mimics compared with control cells. Additional investigations revealed that miR-296-3p was involved in regulating the PI3K/AKT/mTOR signaling pathway, and miR-296-3p mimics decreased the mRNA and protein expression levels of MMP2 and SOX4. In summary, the findings demonstrated that miR-296-3p may function as a tumor suppressor, and inhibits the migration and invasion of NSCLC cells by targeting APEX1. miR-296-3p is therefore a potential therapeutic molecular modulator of NSCLC.
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PMID:miR-296-3p targets APEX1 to suppress cell migration and invasion of non-small-cell lung cancer. 3140 54