Homeobox B2 is a potential prognostic biomarker of glioblastoma

SUMMARY OBJECTIVES HOXB2 is a new prognostic indicator for lung cancer. But it is unclear whether HOXB2 holds an effect in glioblastoma (GBM) progression. The purpose of this article was to probe the influences of HOXB2 on GBM pathogenesis. METHODS HOXB2 expression level and prognostic power in GBM patients were analyzed. Then the mRNA and protein expression levels of HOXB2 in GBM cell lines were tested by qRT-PCR and western blotting. Cell proliferation, invasion, and migration were determined by CCK8 and transwell assay, severally. The protein levels of PI3K/AKT-pathway associated proteins were analyzed by western blotting. RESULTS The results indicated that HOXB2 was distinctly overexpressed in GBM patients and high expression of HOXB2 was related to a poor prognosis. Moreover, the expression of HOXB2 was higher in all GBM cell lines U251, U-87MG, GOS-3 than that in HEB cells (normal control). Meanwhile, decreased expression of p-PI3K and p-AKT were identified after HOXB2 knockdown. CONCLUSIONS These data demonstrated that HOXB2 had a vital role in GBM progression and could serve as a promising target for GBM treatment.

RESUMO OBJETIVOS A HOXB2 é um novo indicador prognóstico para o câncer de pulmão. Mas não está claro se a HOXB2 tem algum efeito na progressão do glioblastoma (GBM). O objetivo deste artigo foi sondar as influências da HOXB2 na patogênese do GBM. MÉTODOS Foram analisados o nível de expressão e o poder prognóstico da HOXB2 em pacientes com GBM. Em seguida, os níveis de expressão proteica e mRNA da HOXB2 em linhagens de células de GBM foram testados por qRT-PCR e western blotting. A proliferação, a invasão e migração celular foram determinadas por CCK8 e ensaios transwell, várias vezes. Os níveis proteicos das proteínas associadas à via PI3K/AKT foram analisados pelo método western blotting. RESULTADOS Os resultados indicaram que havia uma clara superrexpressão da HOXB2 em pacientes com GBM e que a alta expressão da HOXB2 estava relacionada a um prognóstico negativo. Além disso, a expressão da HOXB2 foi mais elevada em todas as linhagens de células do GBM U251, U-87MG, GOS-3 do que nas células HEB (controle normal). Entretanto, a diminuição da expressão de P-PI3K e p-AKT foi identificada após a redução da expressão da HOXB2. CONCLUSÕES Esses dados demonstram que a HOXB2 desempenha um papel vital na progressão do GBM, podendo ser um alvo promissor para o tratamento do GBM.

Relationship between hypospadias and HOXA13, EGF and EGFR genes in children / 中国医师杂志

Objective@#To analyze the relationship between the expression of homeobox A13 (HOXA13), epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR) gene in prepuce tissue of children with congenital hypospadias, discuss the relationship and significance of HOXA13, EGF and EGFR genes in congenital hypospadias and to understand their role in the pathogenesis of hypospadias.@*Methods@#65 cases of hypospadias were selected as the experimental group and 42 cases of phimosis as the control group. Hematoxylin-eosin (HE) staining was used to observe the pathological characteristics of prepuce tissues in the two groups. Immunohistochemistry, real-time fluorescence quantitative polymerase chain reaction (qRT-PCR) and Western blot were used to detect the expression of HOXA13, EGF and EGFR in the two groups.@*Results@#⑴ HE staining showed that the epidermis of hypospadias was composed of keratinized stratified flat epithelium and epidermis of penile skin. The prepuce of phimosis children showed only infiltration of inflammatory cells in the superficial layer of the inner prepuce, blood vessel congestion, no obvious appendage structure, mostly fibroblasts. ⑵ Immunohistochemistry: The positive expressions of HOXA13, EGF and EGFR in the control group were significantly higher than those in the experimental group (P<0.01). ⑶ qRT-PCR: The expression levels of HOXA13, EGF and EGFR in the control group were 53.447±33.471, 80.012±20.430, 75.012±14.339, and the expression levels of HOXA13, EGF and EGFR in the experimental group were 9.128±5.996, 45.521±18.242, 32.043±10.215, respectively. The expression of HOXA13, EGF and EGFR in the control group was significantly higher than that in the experimental group (P<0.01). ⑷ Western blot: The expression levels of HOXA13, EGF and EGFR in the experimental group were lower than those in the control group.@*Conclusions@#The expression of HO-XA13, EGF and EGFR in prepuce tissue of children with hypospadias is low, which may be related to hypospadias.

Relationship between hypospadias and HOXA13, EGF and EGFR genes in children / 中国医师杂志

Objective To analyze the relationship between the expression of homeobox A13 (HOXA13),epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR) gene in prepuce tissue of children with congenital hypospadias,discuss the relationship and significance of HOXA13,EGF and EGFR genes in congenital hypospadias and to understand their role in the pathogenesis of hypospadias.Methods 65 cases of hypospadias were selected as the experimental group and 42 cases of phimosis as the control group.Hematoxylin-eosin (HE) staining was used to observe the pathological characteristics of prepuce tissues in the two groups.Immunohistochemistry,real-time fluorescence quantitative polymerase chain reaction (qRT-PCR) and Western blot were used to detect the expression of HOXA13,EGF and EGFR in the two groups.Results (1) HE staining showed that the epidermis of hypospadias was composed of keratinized stratified flat epithelium and epidermis of penile skin.The prepuce of phimosis children showed only infiltration of inflammatory cells in the superficial layer of the inner prepuce,blood vessel congestion,no obvious appendage structure,mostly fibroblasts.(2) Immunohistochemistry:The positive expressions of HOXA13,EGF and EGFR in the control group were significantly higher than those in the experimental group (P ＜ 0.01).(3) qRT-PCR:The expression levels of HOXA13,EGF and EGFR in the control group were 53.447 ±33.471,80.012 ±20.430,75.012 ± 14.339,and the expression levels of HOXA13,EGF and EGFR in the experimental group were 9.128 ± 5.996,45.521 ± 18.242,32.043 ± 10.215,respectively.The expression of HOXA13,EGF and EGFR in the control group was significantly higher than that in the experimental group (P ＜0.01).(4) Western blot:The expression levels of HOXA13,EGF and EGFR in the experimental group were lower than those in the control group.Conclusions The expression of HOXA13,EGF and EGFR in prepuce tissue of children with hypospadias is low,which may be related to hypospadias.

Expression of HOXB7 protein in colorectal cancer and its clinical significance / 重庆医学

Objective To investigate the expression of HOXB7 in colorectal cancer and its relationship with clinicopathological factors and prognosis.Methods Eighty-seven patients with colorectal cancer were retrospectively analyzed.The expression of HOXB7 mRNA and protein in colorectal cancer tissues was detected by RT-PCR and immunohistochemical methods.Their correlation with clinicopathological parameters and prognosis was analyzed.Results The relative expression level of HOXB7 mRNA in colorectal cancer tissue was(42.4 ± 16.3),which was significantly higher than(19.4 ± 7.6) in the paracancerous normal tissue(P＜0.05).The positive expression rate of HOXB7 protein in colorectal cancer tissues was 73.9％,which was obviously higher than 10.3 ％ in the paracancerous normal tissue (P＜ 0.05);expression of HOXB7 protein was significantly correlated with the TNM stage,lymph node metastasis and distant metastasis(P＜0.05),moreover the patients with HOXB7 positive expression had poorer prognosis.Conclusion HOXB7 protein expression is up-regulated in colorectal cancer tissue,and its high expression is correlated with the clinicopathological factors and prognosis in the patients with colorectal cancer.

The increasedexpression of PDX-1 may improve insulin resis tance in T2DM rats / 中国医师杂志

Objective Pancreatic duodenal homeobox-1 ( PDX-1) plays an important role in the occurrence and development of diabetes.More importantly,its potential application in insulin resistance (IR) improvement is attracting further attention .Berberine has been shown to improve glucose metabolism and insulin resistance .In this study,rat models of type 2 diabetes mellitus ( T2DM) were established by combination of intraperitoneal injection of low -dose streptozotocin and highg-lucose-high-fat diet induction .The effect of berberine on fasting glucose , fasting serum insulin , homeostasis model assessment of insulin resistance ( HOMAI-R) , and ex-pression of PDX -1 of islet in T2DM rats were analyzed .The present study aimed to evaluate the anti-diabetic efficacy of berberine and study the mechanism of its preliminary therapeutic effects .Methods Twenty healthy adult male Sprague Dawley ( SD) rats were di-vided by random number table into the normal control group ( n =6) feeding with a standard diet ,and the experimental group ( n =14 ) given an intraperitoneal injection of streptozotocin .The rats with fasting blood glucose ( FBG) greater than 13.8 mmol/L were ran-domly divided into diabetes mellitus group feeding high sugar high fat diet for two weeks and then continuing with a standard diet , and the berberine group given berberine [180 mg /(kg· d)] every day.The normal control group and diabetes mellitus group were given physiological saline for every day 6 weeks.At the end of 6th week, the rats were executed , and the levels of fasting glucose, fasting se-rum insulin, HOMA-IR, and expression of PDX-1 in pancreas islet of each group were detected .The expression of PDX1-in pancreas islet was examined by immunohistochemistry .The image pro plus 6.0software was used to calculate the integrated optical density ( IOD) of positive expression .Results Compared with the normal control group , FBG, fasting insulin levels ( FINS) , and HOMA-IR of the diabetes mellitus group and berberine group were significantly increased ( P <0.05 ) .Compared with the diabetes mellitus group, FBG, FINS, and HOMA-IR of the berberine group were statistically significantly decreased [ ( 13.11 ±6.87 ) mmol/L vs (18.45 ±4.69) mmol L/, (2.58 ±0.34) μIU/ml vs (2.98 ±0.40) μIU/ml, 1.60 ±0.91 vs 2.75 ±0.28, P <0.05].Compared with the normal control group , the expression of PDX-1 of the islet in the diabetes mellitus group and berberine group was statistically significantly decreased ( P <0.05).After treatment with berberine, FBG, FINS, HOMA-IR, and IOD of PDX-1 in pancreas islet of berberine treatment rats were significantly increased compared with the diabetes mellitus group ( 9.14 ±1.51 vs 6.79 ±0.98 , P <0.01 ) .Conclusions The increases of PDX-1 in islet may be one of the mechanism in the improvement of hyperglycemia .

ZHX2 and cancer / 国际肿瘤学杂志

Transcription repressor ZHX2 is one of the members in ZHX protein family,which exists widely in human tissue and participates in the occurrence and development of various diseases.Researches show that ZHX2 is closely related to the occurrence and development of cancers,such as liver cancer,multiple myeloma,gastric cancer and colorectal cancer,which has the potential value of tumor treatment.

Effects of miR-135a on HOXA10 expression, proliferation and apoptosis of ovarian cancer cells / 中华妇产科杂志

Objective To investigate the effects of miR-135a on HOXA10 expression,proliferation and apoptosis of SKOV3 cells.Methods (1) Through computer-aided algorithms,the predicted target gene of miR-135a (HOXA10)were determined.(2) miR-135a mimics,miR-135a inhibitor and negative control were transfected into SKOV3 cells,respectively.Reverse transcription (RT)-PCR,western blot analysis were used to examine the expression levels of HOXA10 at different times (24,48 and 72 hours).(3) A luciferase reporter assay was used to confirm the direct regulation between miR-135a and HOXA10.(4) SKOV3 cells proliferation at different times (24,48 and 72 hours) was detected by methyl thiazolyl tetrazolium(MTT) assay [quantified by absorbance(A)].Western blot was used to examine the expression of apoptosis-associated protein bcl-2,bax and caspase-3 in SKOV3 cells after 48 hours transfection.Results (1) HOXA10 was predicted to be the target gene of miR-135a by computer-aided algorithms.(2) RT-PCR shown that HOXA10 mRNA levels were decreased over time (24,48 and 72 hours) after miR-135a mimics transfectionin SKOV3 cells (0.94 ±0.04 vs 0.78 ±0.03 vs 0.70 ±0.03,P ＜0.05).While,the expression of HOXA10 mRNA was increased over time after miR-135a inhibitor transfection (1.14 ± 0.05 vs 1.16 ±0.03 vs 2.60 ±0.08,P ＜0.05).After transfected with miR-135a mimics or miR-135a inhibitor over 48 and 72 hours,the HOXA10 expression levels in SKOV3 cells were significantly lower or higher than each control group,respectively (all P ＜ 0.01).Western blot analysis of HOXA10 expression in SKOV3 cells confirmed the results of RT-PCR detected.(3) After cotransfection of miR-135a plasmid and pMIR-REPORT luciferase plasmid containing HOXA10,luciferase reporter assays showed that the luciferase activity reduced by 67.8％ (P ＜0.01).(4) MTT showed that SKOV3 cells growth after miR-135a mimics transfection for 48 and 72 hours were significantly lower than those in control group (0.38 ± 0.03 vs 0.52 ± 0.05,0.67 ±0.05 vs 0.75 ± 0.06 ; respectively,all P ＜ 0.05).While,SKOV3 cells transfected with miR-135a inhibitor for 72 hours grew significantly faster than that in control group (0.95 ± 0.05 vs 0.75 ± 0.06,P ＜ 0.01).After miR-135a mimics transfection,the level of bcl-2 protein was significantly lower than that in control group (0.28 ±0.06 vs 0.76 ±0.09,P ＜0.01).The activity of caspase-3 was significantly higher than that in control group (115.0 ± 2.4 vs 95.4 ± 2.1,P ＜ 0.01).While,there was no statistical difference of bax expression (P =0.142).However,after miR-135a inhibitor transfection,the expression level of bcl-2 protein was significantly higher than that in control group (0.92 ± 0.03 vs 0.76 ± 0.09,P =0.037) and the activity of caspase-3 was significantly lower than that in control group (59.5 ± 4.1 vs 95.4 ± 2.1,P ＜ 0.01).There was also no statistical difference of bax expression (P =0.066).Conclusion miR-135a may play an important role in cell proliferation and apoptosis of ovarian cancer cells by regulating HOXA10 and its downstream pathways.

The role of p38 signal transduction pathway in the pathogenesis of Barrett esophagus / 中华消化杂志

Objective To investigate the role of deoxycholic acid (DCA) in the pathogenesis of Barrett esophagus.Methods Normal human esophageal mucosal epithelial cells were cultured in vitro with defined keratinocyte serum-free media (D-KSFM).The cultured cells were treated with different concentrations of DCA and specific p38 mitogen activated protein kinase (MAPK) inhibitor. The expression of p38,phosphorylated p38 (p-p38) and caudal-related homeodomain transcription 2 (CDX2) at protein level were assessed by Western blot.The correlation between p-p38 and CDX2 was analyzed.The data were analyzed by one way ANOVA and LSD test.Results After being cultured with DCA for 24 h,the expression of p-p38 and CDX2 increased along with the increasing of DCA concentration.Compared with the control group (p-p38 was 13.7％ ± 1.0％ and CDX2 protein was 0),the difference was statistically significant (P＜ 0.05).When DCA was at 500 μmol/L,the expression of p-p38 and CDX2 reached the highest level (44.0％ ± 1.7％ and 8.59± 1.25).After pretreated with SB203580 for two hours and then 500 μmol/L DCA was added into cell culture,both expression level of p-p38 and CDX2 decreased compared with 500μmol/L DCA group (p-p38:28.3％ ±2.2％ vs50.5％±9.5％,CDX2:0.94±0.13 vs 2.31±0.41) after 24 h.Conclusions DCA can induce the expression of CDX2 in normal human esophageal mucosal epithelial cells,which is related with the activation of p38.The phosphorylation of p38 maybe involved in the pathogenesis of Barrett esophagus.

The expression and significance of CDX2 and Ki-67 in colorectal tumor / 中国医师杂志

ObjectiveTo investigate the expression and significance of CDX2,Ki-67 in adenoma and colorectal adenocarcinoma,and the correlation between CDX2 and Ki-67.MethodsThe expression of CDX2 and Ki-67 was evaluated in the colorectal adenocarcinoma,adenoma and normal colorectal mucosa as control subjects by immunohistochemistry.ResultsThe magnitude of CDX2 were negatively correlated with the level of dysplasia in adenoma(rs=-0.38,P =0.02),and negatively correlated with differentiation,lymph node metastasis,diversion and Dukes stage of cancer in colorectal adenocarcinoma(rs=-0.49,rs=-0.37,rs =- 0.38,rs =-0.37,P =0.01).The expression and relativity of Ki-67 in the samples were contrary to the CDX2.The levels of CDX2 and Ki-67 expression had significant difference between the adenoma and adenocarcinoma,and showed negatively correlation in this two type tissues (rs=-0.69,P =0.00; rs =-0.40,P =0.00).ConclusionsCDX2 may be used as an effective marker to evaluate malignancy degree and prognosis of large bowel neoplasm patient.The levels of Ki-67 expression in colorectal adenocarcinoma are correlated with malignancy degree and clinical stage.The expression of CDX2 is negatively correlated with Ki-67.Combined detection of CDX2 and Ki-67 may be helpful for the judgment of colorectal tumor biological characters.

Homeodomain-interacting protein kinase 2 and tumor signal transduction / 国际肿瘤学杂志

Homeodomain-interacting protein kinase 2(HIPK2)is a member of a member of the serine/threonine protein kinase family which localized in the mucleus.It is not only involved in advanced stage embryogenesis,development of nerve tissue,retina and muscular tissue,but also takes part in regulation of tumor signaling transduction,down-modulated expression of oncogene,induced apoptosis of tumor cells,and inhibited angiogeuesis of tumor.The regulation of HIPK2 in tumor signaling transduction pathway is associated with P53 signaling,Wnt/β-catenin pathway and hypoxia.

Expression and significance of HOXA10 gene in the eutopic and ectopic endometrium of endometriosis / 中华妇产科杂志

Objectives To investigate the expression and clinical significance of HOXA10 gene in the eutopic and ectopic endometrium of endometriosis.Mehtods Between Jan.2009 to Aug.2010,30 patients with endometriosis undergoing laparoscopic surgery in Maternal and Children's Hospital of Foshan.Eutopic and ectopic endometrium were obtained.In the mean time,30 patients with benign ovary cyst or tubal infertihty undergoing laparoscopic surgery were selected as controls.Their uterine endometrium were obtained real-time fluorescent quantitation,western blot and immunohistochemistry technique were used to detect mRNA and protein expression of HOXA10 gene in the eutopic endometrium group,ectopic endometrium group and control group.Results The mRNA and protein expression of HOXA10 gene were 0.61 ±0.07 and 0.47 ±0.05 in the eutopic endometrium of endometriosis,0.64 ±0.06 and 0.50 ±0.05 in ectopic endometrium of endometriosis,which were significantly lower than 1.22 ± 0.14 and 1.42 ± 0.14 in control group ( P ＜ 0.01 ).However,the mRNA and protein expression of HOXA 10 between eutopic and ectopic endometrium of endometriosis did not reach statistical difference ( P ＞ 0.05 ).The expression of HOXA10 in eutopic and ectopic endometrium of endometriosis were decreased by immunohistochemistry staining.Conclusion The lower expression of HOXA10 gene in the eutopic and ectopic endometrium of endometriosis might be associated with pathogenesis and infertility of endometriosis.

Análise da expressão dos genes PROP1 e CTNNB1 em craniofaringiomas adamantinomatosos com e sem mutação somática no CTNNB1 / Analysis of PROP1 and CTNNB1 expression genes in adamantinomatous craniopharyngiomas with and without CTNNB1 somatic mutation

Os craniofaringiomas são os tumores mais frequentes da região hipotálamohipofisária na faixa etária pediátrica. Apesar de serem histologicamente benignos, sua tendência infiltrativa e seu comportamento agressivo resultam em significante morbimortalidade. Histologicamente podem ser divididos em dois subtipos: adamantinomatosos e papilíferos. A patogênese dos craniofaringiomas é pouco compreendida. Mutações no gene CTNNB1, que codifica a proteína beta-catenina, são a única alteração molecular conhecida até o momento implicada na tumorigênese dos craniofaringiomas adamantinomatosos. Tais mutações afetam o sítio de degradação da beta-catenina, que passa a se acumular no citoplasma e no núcleo, ativando excessivamente a via de sinalização WNT, através da ligação aos fatores de transcrição da família LEF/TCF, levando a tumorigênese. Recentemente foi descoberto um novo mecanismo de determinação da linhagem celular hipofisária regulado pela beta-catenina, através do qual ela interage diretamente com o PROP1 para determinar a diferenciação celular hipofisária. De acordo com esse modelo, o complexo protéico PROP1/beta- catenina atua simultaneamente como repressor do HESX1 e ativador do PIT1, dependendo dos co-fatores associados. Pacientes com mutações germinativas inativadoras no PROP1 desenvolvem hipopituitarismo e podem apresentar aumento hipofisário com imagens de ressonância nuclear magnética (RNM) da região selar muitas vezes semelhantes àquelas dos craniofaringiomas, com hiperssinal em T1. Por outro lado, camundongos com expressão persistente do Prop1 exibem defeitos na regulação da proliferação celular hipofisária, incluindo cistos da bolsa de Rathke, hiperplasia adenomatosa e tumores, sugerindo que mutações com ganho de função no PROP1 também poderiam contribuir para a patogênese de tumores hipofisários em seres humanos. A semelhança entre as imagens de RNM dos pacientes com craniofaringiomas e daqueles com aumento hipofisário devido a mutações...

Craniopharyngiomas are the the commonest tumors to involve the hypothalamo-pituitary regions in childhood population. Histologically they are benign, and can be divided in two primary subtypes: the adamantinomatous and the papillary. Although histologically benign, their infiltrative tendency and aggressive behavior can result in great morbidity. The pathogenesis of craniopharyngiomas is poorly understood. To date, beta-catenin gene (CTNNB1) mutations have been identified only in the adamantinomatous subtype. These mutations affect the degradation target box of beta-catenin that accumulates in the cytoplasm and the nucleus increasing the transcriptional activity of WNT pathway through interaction with the transcription factors of LEF/TCF family, leading to tumorigenesis. Recently, an interaction between beta-catenin and PROP1 was described as a new mecanism for beta-catenindependent regulation of pituitary cell-lineage determination. According to this novel model, the PROP1/beta-catenin proteic complex would act as a binary switch to simultaneously repress the transcription factor HESX1 and to activate expression of transcription factor PIT1, depending on the associated cofactors. Patients with loss-of-function mutations in PROP1 present combined pituitary hormonal deficiency generally associated with pituitary enlargement and the magnetic resonance imaging (MRI) of the sellar region in these patients sometimes resembles that of the craniopharyngiomas, with T1 hyperintense signal. On the other hand, transgenic mice with persistent Prop1 expression exhibit defects consistent with misregulation of pituitary cell proliferation, including adenomatous hyperplasia with formation of Rathke's cleft cysts and tumors suggesting that misregulation of PROP1 expression in human could contribute to pathogenesis of pituitary tumors. The similarity between the MRI images of craniopharyngiomas patients and that of patients with loss-of-function mutations in...

Hipopituitarismo congénito: experiencia en 23 casos / Congenital hypopituitarism: report of 23 cases

Background: Congenital hypopituitarism is an uncommon cause of hypophyseal insufficiency It is less common than growth hormone deficiency which has an incidence of 1:4.000 to 1:8.000 Uve newborns. Early diagnosis ofthis condition is important to prevent impairment of cognitive function, poor growth and alterations in metabolic profile in these patients. Aim: To report 23 patients diagnosed with congenital hypopituitarism. Material and methods: Retrospective review of clinical records of 23 patients (12 males) with congenital hypopituitarism, diagnosed during a 21 years period. In a group of 16 patients a molecular study was performed searching for mutations in HESX1, PROP-1 or POUF-1. Results: Short stature was the most frequent sign at the first evaluation, followed by neonatal hypoglycemia and presence of nistagmus, strabismus, atrophic optic nerve or malformations in the middle Une showed in CNS imaging, suggesting septo-optic-dysplasia. All male patients diagnosed during neonatal period, exhibited micropenis. CNS images showed isolated hypophyseal hypoplasia or associated to an ectopic neurohypophysis in most patients. No patient in the subgroup subjected to molecular analysis had any of the mutations in the searched genes. Conclusions: The diagnosis of hypopituitarism must be based on clinical grounds, speciaUy when hypoglycemia, prolonged jaundice, micropenis or midline alterations are found in the neonatal period.