Maternal factors and preoperative nutrition in children with mild cases of congenital heart disease.

AIM: The preoperative poor nutrition of children with congenital heart disease (CHD) impacts the postoperative rehabilitation process of pediatric CHD cases. The factors of these children's preoperative poor nutrition, excluding the disease, have been underreported. The aim was to investigate the preoperative nutritional status of children with CHD who required a simple surgical repair and to analyze the maternal characteristics that are associated with poor nutrition in these sick children. METHODS: This was a cross-sectional survey. The weight and height of the children were measured, maternal data were collected via a questionnaire and a univariate analysis and multivariate logistic regression were used to analyze the association between maternal factors and the preoperative poor nutrition of the children with CHD. RESULTS: A total of 119 children with simple CHD were recruited to the study. The prevalence of poor nutrition was higher in the children with CHD ("cases") than in the healthy children ("controls"). An increased risk of poor nutrition was associated with lower mothers' perception, education level, understanding of the disease, and higher anxiety. CONCLUSIONS: Paying attention to maternal anxiety, depression, and knowledge and providing interventions for the mothers of children with CHD are important in order to promote the nutritional status of these children.

Eugenol protects the transplanted heart against ischemia/reperfusion injury in rats by inhibiting the inflammatory response and apoptosis.

The aim of the present study was to investigate the protective effect of eugenol on the transplanted heart and explore its mechanisms of action. Male Sprague-Dawley rats were randomly divided into a sham group (n=10), a eugenol group (n=10 pairs, donors and recipients) and a control group (n=10 pairs, donors and recipients). The recipients in the eugenol group received an intraperitoneal injection of eugenol (20 mg/kg/day). The sham group and the control group received equal volumes of physiological saline by intraperitoneal injection. After 15 days the recipients in the control and eugenol groups underwent abdominal heterotopic heart transplantation, while the sham group received only a coeliotomy. The orthotopic hearts in the sham group and the heterotopic hearts in the eugenol and control groups, as well as the peripheral blood samples from all three groups were taken 3 h post operation for biochemical, histopathological, molecular and apoptosis analyses. Compared with the control group, the eugenol treatment significantly reduced the myocardial malondialdehyde content, serum cardiac troponin I, creatine kinase-MB, tumor necresis factor-α and interleukin-6 levels (P<0.05) and significantly alleviated myocardial injury. Western blot analysis demonstrated that the protein expression of cleaved Poly (ADP-ribose) polymerase 1, BAX and active caspase-3 in the eugenol group were significantly decreased, while B-cell lymphoma 2 expression was significantly increased compared with the control group (P<0.05). The myocardial apoptosis rate of the eugenol group was significantly decreased compared with the control group (P<0.05). In conclusion eugenol treatment significantly reduced myocardial injury and demonstrated protective effects for the transplanted heart.

[Preoperational nutritional status for the children with congenital heart disease and the influential factors].

OBJECTIVE: To investigate the preoperational nutritional condition for the children with congenital heart disease, and to analyze the relevant factors.
 Methods: According to the standards of WHO, the Z-scores was used to assess the nutritional condition for the children, and the generational information questionnaire, State-Trait Anxiety Inventory, Self-Rating Depression Scale and Parent Understanding Questionnaire were used to analyze the maternal factors.
 Results: Stunting, underweighting and wasting represented the poor nutritional conditions, which accounted for 28.6%, 25.3% and 25.3%, respectively. Maternal accurate perception and the psychological problems such as anxiety and depression were the main relevant factors.
 Conclusion: The poor nutritional condition for the congenital heart disease was serious. It is very important to improve the maternal accurate perception and to relieve the maternal psychological problems for changing the nutritional condition through appropriate health education and effective intervention.

Survival and prognostic factors in Chinese patients with osteosarcoma: 13-year experience in 365 patients treated at a single institution.

This study was designed to retrospectively analyze the survival and prognostic factors in Chinese osteosarcoma patients received neoadjuvant chemotherapy or/and surgery in a single institution. A total of 365 patients with pathological proved osteosarcoma undergoing neoadjuvant chemotherapy or/and surgery in a single institution between December 1999 and December 2012 were retrospectively analyzed for the demographic, tumor-related, and treatment-related variables, prognostic factors for survival rate and chemotherapy response. There were 231 males and 134 females (ratio, 1.72:1). The average age was 21±10years, with peak age between 10 and 20 years old (62%, 226/365). Of 365 patients, 319 (87.4%) suffered from primary tumor only, and 46 (12.6%) had metastases upon initial presentation. The overall 5-year survival rate was 65%. Upon univariate analysis, tumor site (femur 60.3%; other long bone 70.2%; trunk 33.6%; P=0.012), primary metastases (yes 36.7%; no 68.9%; P=0.000), tumor response to preoperative chemotherapy (good 89.8%; poor 47.5%; P=0.001) and recurrence/metastases after treatment (yes 36.2%; no 63.8%; P=0.000) were associated with higher 5-year survival rate. All factors except tumor site maintained their significance in multivariate testing. Male sex and nonconventional subtype of tumor were related to a higher likelihood of poor chemotherapy response.The absence of metastases at initial presentation, negative local recurrence or metastases after treatment, and tumor response to chemotherapy are of independent prognostic value in osteosarcoma. The overall prognostic factors and survival in Chinese patients are similar to those patients reported in western countries.

Predictive Immunohistochemical Markers Related to Drug Selection for Patients Treated with Sunitinib or Sorafenib for Metastatic Renal Cell Cancer.

Targeted drug decisions in metastatic renal cell carcinoma are exclusively made on the basis of clinical criteria. We investigated whether these biomarkers (HIF-1α, HIF-2α, CAIX, VEGF, VEGFR1, VEGFR2, VEGFR3, PDGFB, PDGFRA, PDGFRB, CD31, CD44, bcl-xL, KIT, p21, CXCR4, PTEN, (CSF)-1R, RET, and FLT-3) can predictive the different effects between sunitinib and sorafenib treatments and are available to guide targeted drug selection. We enrolled all patients who underwent nephrectomy with postoperative sunitinib- or sorafenib-treatment at our institution from 2007 to 2012. Immunohistochemical approach was applied to assess the potential differential effects of immunostainings between sunitinib- and sorafenib-treated groups. We found that patients with high HIF-2α, CD31 expression showed greater relative PFS and OS benefit and patients with high CAIX expression presented greater relative OS benefit from sunitinib than from sorafenib, patients with high VEGFR1 or PDGFRB expression levels exhibited worse relative PFS benefit from sunitinib than from sorafenib. Namely high HIF-2α, CD31, and CAIX expression levels along with low VEGFR1 and PDGFRB expression levels improved the benefit of sunitinib treatment compared with sorafenib treatment. These results can identify whether patients can benefit more from sunitinib or sorafenib for drug selection guidance, eventually with precision medicine.

Rare and curable renin-mediated hypertension: a series of six cases and a literature review.

BACKGROUND: Reninoma is an extremely rare renal tumor characterized by excessive renin secretion causing secondary hypertension and hypokalemia. Reninoma is a benign and highly manageable lesion if it is discovered early and removed surgically. METHODS: We report six cases of reninoma and provide a literature review on this rare disease, highlighting the diagnostic evaluation and follow-up of each patient. RESULTS AND CONCLUSIONS: Reninoma should be considered in young adults with elevated renin activity and refractory hypertension. Imaging studies and selective venous catheterization are often helpful in identifying the lesion. In most cases of reninoma presenting with renin-mediated hypertension, conservative surgical treatment should be considered to remove the small, superficial lesion.

Two-stage resection of a disseminated mixed endometrial stromal sarcoma and smooth muscle tumor with intravascular and intracardiac extension.

OBJECTIVE: Mixed endometrial stromal and smooth muscle tumor (MESSMT)-a rare mesenchymal uterine tumor of the uterus with atypical clinical symptoms-is susceptible to misdiagnosis and missed diagnosis. We report a case of a disseminated MESSMT with intravenous and intracardiac extensions treated with staging surgery and review previously documented cases of such tumors with intracardiac extension. CASE REPORT: The case involves a 45-year-old woman with disseminated MESSMT that originated in the uterus and progressed through the iliac vein, inferior vena cava, right atrium, and into the right ventricle, which closely resembled intravenous leiomyomatosis (IVL) grossly and microscopically. She presented with a 1-year history of dyspnea on exertion. IVL was highly suspected preoperatively based on computed tomography and magnetic resonance imaging findings. Two-stage surgeries were performed successfully. The postoperative pathology indicated a disseminated MESSMT. CONCLUSION: This case illustrates the important role of pathology and immunohistochemistry in the differential diagnosis of a rare tumor that mimics the characteristics of IVL with intracardiac involvement and demonstrates the therapeutic strategy for this rare entity.

CT characteristics and pathological implications of early stage (T1N0M0) lung adenocarcinoma with pure ground-glass opacity.

OBJECTIVES: To analyze the CT characteristics and pathological classification of early lung adenocarcinoma (T1N0M0) with pure ground-glass opacity (pGGO). METHODS: Ninety-four lesions with pGGO on CT in 88 patients with T1N0M0 lung adenocarcinoma were selected from January 2010 to December 2012. All lesions were confirmed by pathology. CT appearances were analyzed including lesion location, size, density, uniformity, shape, margin, tumour-lung interface, internal and surrounding malignant signs. Lesion size and density were compared using analysis of variance, lesion size also assessed using ROC curves. Gender of patients, lesion location and CT appearances were compared using χ²-test. RESULTS: There were no significant differences in gender, lesion location and density with histological invasiveness (P > 0.05). The ROC curve showed that the possibility of invasive lesion was 88.73% when diameter of lesion was more than 10.5 mm. There was a significant difference between lesion uniformity and histological invasiveness (P = 0.01). There were significant differences in margin, tumour-lung interface, air bronchogram with histological invasiveness ( P = 0.02,P = 0.00,P = 0.048). The correlation index of lesion size and uniformity was r = 0.45 (P = 0.00). CONCLUSIONS: The lesion size and uniformity, tumour-lung interface and the air bronchogram can help predict invasive extent of early stage lung adenocarcinoma with pGGO. KEY POINTS: • CT characteristics and pathological classification of pGGO lung adenocarcinoma smaller than 3 cm • The optimal cut-off value for discriminating preinvasive from invasive lesions was 10.5 mm • Uniformity was significant difference between histological subtypes and correlated with lesion size • Tumour margin, tumour-lung interface and air bronchogram showed different between histological types • No significant difference in gender, lesion location and density with histological subtypes.

[Effect of verapamil and nitroglycerin on transplanted lung function in canines].

OBJECTIVE: To investigate the protective effect of combined administration of verapamil and nitroglycerin on the function of canine transplanted lungs. METHODS: Twenty orthotopic left lung transplantations were performed in 40 canines, which were randomly divided into 4 groups. In group I (control), the donor lungs were perfused and preserved with LPD solution, while group II with LPD solution plus verapamil 0.1 g/L, group III with LPD solution plus nitroglycerin 0.1g/L, and group IV with LPD solution plus verapamil 0.1 g/L and nitroglycerin 0.1 g/L. Hemodynamics and graft gas exchange were assessed 0, 2 and 4 h after the operation. The lung grafts were harvested to measure the wet/dry weight ratio, malondialdehyde (MDA) contents and superoxide dismutase (SOD) activity. RESULTS: Compared with group I, II and III, the mean pulmonary artery pressure (MPAP), pulmonary vascular resistance index (PVRI), partial pressure of oxygen in arterial blood (PaO2), dynamic compliance (Cdyn) and alveolar-arterial oxygen tension volume [P(A- a)O2] in group IV were improved significantly (P<0.05). No significant difference in the partial pressure of carbondioxide (PaCO2) and peak inspiratory pressure (PIP) was observed in the 4 groups (P>0.05). In group IV, the wet/dry weight ratio and MDA contents were lower than those in the other 3 groups, and the SOD activity was significantly higher than that of the other 3 groups (P<0.05). CONCLUSION: Verapamil and nitroglycerin in LPD solution can protect the respiratory function of canine lung grafts by attenuating pulmonary edema and oxidative stress.

Screening preoperative peptide biomarkers for predicting postoperative myocardial infarction after coronary artery bypass grafting.

Postoperative myocardial infarction (PMI) is one of the most serious complications of cardiac surgeries. No preoperative biomarker is currently available for predicting PMI after cardiac surgeries. In the present study, we used a phage display peptide library to screen potential preoperative peptide biomarkers for predicting PMI after coronary artery bypass grafting (CABG) surgery. Twenty patients who developed PMI after CABG and 20 age-, sex-, and body mass index-matched patients without PMI after CABG were enrolled as a discovery cohort. Another 50 patients who developed PMI after CABG and 50 randomly selected patients without PMI after CABG were enrolled as a validation cohort to validate the potential peptide biomarkers identified in the discovery cohort. Fifty randomly selected healthy volunteers were also enrolled in the validation phase as a healthy control group. In the discovery/screening phase, 17 out of 20 randomly selected phage clones exhibited specific reaction with purified sera IgG from the PMI group, among which 11 came from the same phage clone with inserted peptide sequence GVIMVIAVSCVF (named PMI-1). In the validation phase, phage ELISA showed that serum IgG from 90% of patients in the PMI group had a positive reaction with PMI-1; in contrast, only 14% and 6% of patients in the non-PMI group and the healthy control group had a positive reaction with PMI-1, respectively. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of the PMI-1 phage clone to preoperatively identify patients who would develop PMI after CABG were 90.0%, 86.0%, 86.5, 89.5% and 88.0%, respectively. The absorbance value of the PMI-1 phage clone showed statistically significant correlation with the peak postoperative serum cardiac troponin I level (r = 0.349, p = 0.012) in the PMI group. In conclusion, we for the first time identified a mimic peptide (PMI-1) with high validity in preoperative prediction of PMI after CABG.

GdX/UBL4A specifically stabilizes the TC45/STAT3 association and promotes dephosphorylation of STAT3 to repress tumorigenesis.

Impaired phosphatase activity contributes to the persistent activation of STAT3 in tumors. Given that STAT family members with various or even opposite functions are often phosphorylated or dephosphorylated by the same enzymes, the mechanism for STAT3-specific dephosphorylation in cells remains largely unknown. Here, we report that GdX (UBL4A) promotes STAT3 dephosphorylation via mediating the interaction between TC45 (the nuclear isoform of TC-PTP) and STAT3 specifically. GdX stabilizes the TC45-STAT3 complex to bestow upon STAT3 an efficient dephosphorylation by TC45. Inasmuch, GdX suppresses tumorigenesis and tumor development by reducing the level of phospho-STAT3 (p-STAT3), whereas deletion of GdX results in a high level of p-STAT3 and accelerated colorectal tumorigenesis induced by AOM/DSS. Thus, GdX converts TC45, a nonspecific phosphatase, into a STAT3-specific phosphatase by bridging an association between TC45 and STAT3.

CHIP/Stub1 functions as a tumor suppressor and represses NF-κB-mediated signaling in colorectal cancer.

The carboxyl terminus of Hsc70-interacting protein (CHIP, also named Stub1), a U-box containing E3 ubiquitin ligase, is involved in degradation of certain oncogenic proteins. Recent studies indicated that CHIP suppresses tumor progression in human cancers by targeting Src-3, hypoxia inducible factor 1α, NF-κB, ErbB2 and c-Myc. Here, we report that CHIP was downregulated, predominantly, in the late stages of human colorectal cancer (CRC), and that the CHIP promoter was hypermethylated in CRC specimens. Overexpression of CHIP in HCT-116 cells resulted in impaired tumor growth in nude mice and decreased abilities of tumor cell migration and invasion. Conversely, depletion of CHIP in HCT-116 cells promoted tumor growth and increased tumor cell migration and invasion. CHIP was further found to negatively regulate NF-κB signaling in HCT-116 cells by promoting ubiquitination and degradation of p65, a subunit of the NF-κB complex. The suppressive effect of CHIP led to decreased expression of NF-κB-targeted oncogenes including Cyclin D1, c-Myc, MMP-2, VEGF and IL-8. We proposed that CHIP inhibits the malignancy of CRC cells, possibly through targeting NF-κB signaling. This study provides functional evidence for CHIP as a potential tumor suppressor in CRC, and CHIP expression may be a marker for stages of CRC.

Epigallocatechin gallate promotes p53 accumulation and activity via the inhibition of MDM2-mediated p53 ubiquitination in human lung cancer cells.

Epigallocatechin gallate (EGCG), which is derived from green tea, is well known for its chemopreventive activity. Several studies have shown that p53 plays an important role in the activity of EGCG; however, the mechanism by which EGCG regulates p53 requires further investigation. In the present study, we showed that EGCG inhibits anchorage-independent growth of human lung cancer cells by upregulating p53 expression. EGCG treatment can substantially increase p53 stability, promote nuclear localization of p53 and decrease nuclear accumulation of MDM2. We also found that EGCG increases the phosphorylation of p53 at Ser15 and Ser20 and enhances its transcriptional activity. Although EGCG promotes MDM2 expression in a p53-dependent manner, the interaction between MDM2 and p53 was significantly inhibited following EGCG treatment, which resulted in the inhibition of MDM2-mediated p53 ubiquitination. Thus, our results suggest that the stabilization and activation of p53 may partly contribute to the anticancer activity of EGCG.

Rosai-Dorfman disease: a retrospective analysis of 13 cases.

BACKGROUND: Rosai-Dorfman disease (RDD) is a rare, idiopathic, histiocytic proliferative disorder, the infrequent occurrence of which limits in-depth studies. Consequently, many characteristics of this disease remain unknown, restricting early diagnosis and proper treatment. METHODS: In this study, the literature was reviewed and a retrospective analysis of the medical records of 13 patients with RDD conducted to investigate the demographic data, clinical data, laboratory and imaging results, treatment, and prognosis of this disease. RESULTS: Of the 13 cases in our sample, 10 (77%) were purely extranodal RDD, 2 (15%) were both nodal and extranodal, and 1 (8%) was purely nodal. The locations of the 10 purely extranodal RDD lesions included the central nervous system (n = 6, 60%), nasal cavity and paranasal sinuses (n = 3, 30%), and the cutis (n = 1, 10%). The locations of the central nervous system-related RDD lesions included the cerebral subdura (n = 2, 29%), the sellar region (n = 3, 14%), the cerebral parenchyma (n = 1, 14%) and the spinal subdura (n = 1, 14%). Ten patients (77%) had stable conditions, 3 (23%) experienced recurrence, and 2 (15%) experienced recurrence and lesion metastasis. CONCLUSIONS: RDD is rare, requiring knowledge of its clinical manifestations for a rapid and correct diagnosis. In light of the possibility of recurrence and lesion metastasis, long-term follow-up is needed. Treatment is still controversial. Future efforts should be directed at investigating the etiology and postoperative treatment for relapsing cases or those with subresected lesions.

CREPT accelerates tumorigenesis by regulating the transcription of cell-cycle-related genes.

Tumorigenesis is caused by an uncontrolled cell cycle and the altered expression of many genes. Here, we report a gene CREPT that is preferentially expressed in diverse human tumors. Overexpression of CREPT accelerates tumor growth, whereas depletion of CREPT demonstrates a reversed effect. CREPT regulates cyclin D1 expression by binding to its promoter, enhancing its transcription both in vivo and in vitro, and interacting with RNA polymerase II (RNAPII). Interestingly, CREPT promotes the formation of a chromatin loop and prevents RNAPII from reading through the 3' end termination site of the gene. Our findings reveal a mechanism where CREPT increases cyclin D1 transcription during tumorigenesis, through enhancing the recruitment of RNAPII to the promoter region, possibly, as well as chromatin looping.

The bone morphogenetic protein antagonist Gremlin is overexpressed in human malignant mesothelioma.

Gremlin is a member of the bone morphogenetic protein (BMP) antagonist family and its antagonistic effect is likely through direct binding to BMP proteins. As an antagonist of BMP, Gremlin plays a role in regulating organogenesis, body patterning and tissue differentiation. Recent studies have shown a deregulation of Gremlin in several types of human cancers. However, the role of Gremlin in human malignant mesothelioma (MM) is still unknown. In this study, we investigated the expression of Gremlin in human MM. We found that Gremlin mRNA and protein were both overexpressed in the majority of primary MM tissue samples that we examined. We also observed high level expression of the Gremlin gene in 4 of the 6 MM cell lines. Consistently, we found that the Gremlin promoter activity was significantly elevated in those MM cell lines expressing the Gremlin gene. On the other hand, no activity of the Gremlin promoter was detected in the two MM cell lines lacking Gremlin expression. Moreover, to examine the functional significance of the Gremlin overexpression in MM, we used shRNA to knock down Gremlin expression in MM cell lines expressing Gremlin and found that inhibition of Gremlin expression significantly suppressed proliferation of those MM cells. Taken together, our results suggest that the BMP antagonist Gremlin is overexpressed in MM and that aberrant activation of Gremlin may play a critical role in the tumorigenesis of human MM.

Magnetic resonance imaging is appropriate for determining the osteotomy plane for appendicular osteosarcoma after neoadjuvant chemotherapy.

There are no standard criteria for determining a sufficient resection margin in the treatment of osteosarcoma. The purposes of this study are to evaluate clinical outcomes using T1-weighted magnetic resonance imaging (MRI) for determining the margin of resection and to compare that with the results of different imaging modalities. Seventeen patients diagnosed with osteosarcoma who underwent en bloc resection with a margin of 2-3 cm based on T1-weighted MRI following chemotherapy were studied. Imaging modalities including conventional radiography, MRI, computed tomography (CT), visual assessment, and histopathological examination were performed and compared. Survival rates were determined. After follow-up of 45.5 ± 13.8 months, no local tumor recurrence was observed in any patient. The 1-, 3-, and 5-year survival rates were 94.1, 82.3, and 76.5%, respectively. The differences in the measurement errors among the five methods were analyzed using pathology as the gold standard. Errors were smallest using T1-weighted and fat-suppressed MRI. There were no significant differences between the measurement results of postoperative histopathological examination and that of T1-weighted imaging or T2 fat-suppressed imaging. The measurement results of radiography and CT were significantly different from that of postoperative pathological findings (P < 0.05). Thus, MRI examination is superior to radiography and CT for determining tumor invasion in patients with osteosarcoma. A resection margin of 2-3 cm determined by MRI provides adequate treatment, while minimizing tissue removal.

Generation of mice with conditional null allele for GdX/Ubl4A.

GdX (also named Ubl4A) is a house-keeping gene located on the X chromosome and encodes a protein harboring an ubiquitin-like domain in human and mouse. Although identified in 1988, the function of GdX remains unknown. To elucidate the role of GdX in vivo, we generated a conditional GdX knockout mouse in which Exon 2 was flanked by two loxP sites. We obtained viable and fertile mice with homozygous GdX(flox/flox) or GdX(flox/Y) allele. Germ-line transmission was confirmed by crossing the mouse bearing conditionally targeted allele with an EIIα-Cre transgenic mouse. GdX was successfully depleted in tissues of EIIα-Cre-GdX-null mice. GdX(-/-) and GdX(-/Y) mice are viable and exhibit normal development compared with wild-type littermates within 6 months during our observation. We also observed that GdX knockout male mice were functionally normal in the reproductive system where Ubl4B was specifically expressed. GdX(flox/flox) and GdX(flox/Y) conditional mice provide a tool for further tissue-specific function analysis of the GdX protein under different conditions.

HSulf-1 inhibits cell proliferation and invasion in human gastric cancer.

The HSulf-1 gene encodes an extracellular 6-O-endosulfatase and regulates the sulfation status of heparan sulfate proteoglycans (HSPG). We have demonstrated that promoter hypermethylation is correlated with the HSulf-1 silencing in gastric cancer. To investigate the functional importance of HSulf-1 silencing in gastric cancer, we restored HSulf-1 expression in the gastric cancer cell line MKN28, which lacks endogenous HSulf-1. Following restoration of expression, HSulf-1 inhibited cell proliferation, motility, and invasion in vitro, as well as significantly suppressing the MKN28 xenograft model (P < 0.05). No noticeable changes in proliferation and motility were observed following restoration of HSulf-1 in another gastric cancer cell line, namely AGS cells. Interestingly, in MKN28 cells, which have been reported to be dependent on extracellular Wnt signaling, we found that HSulf-1 inhibited the transcriptional activity of the Wnt / ß-catenin pathway and downregulated its targeted genes. Conversely, in AGS cells, in the constitutive Wnt / ß-catenin pathway is active, HSulf-1 had no effect on the activity of the Wnt / ß-catenin pathway. Furthermore, transfection of Wnt3a cDNA or ß-catenin shRNA resulted in rescue or enhancement, respectively, of the effects of HSulf-1 in MKN28 cells. Furthermore, HSPG epitope analysis confirmed that HSulf-1 affected the structure of heparan sulfate on the cell surface. Together, the results of the present study suggest that extracellular HSulf-1 may function as a negative regulator of proliferation and invasion in gastric cancer by suppressing Wnt / ß-catenin signaling at the cell surface.

GABARAPL1 negatively regulates Wnt/ß-catenin signaling by mediating Dvl2 degradation through the autophagy pathway.

Wnt signaling is critical for many biological processes and is tightly regulated. In this study, we found that GABARAPL1 (GABA(A) receptor-associated protein like 1, GABARAPL1) interacts with Dvl2 by both yeast two-hybrid screening and immunoprecipitation experiments. Furthermore, we observed that p62 is required for the interaction of Dvl2 and GABARAPL1. Luciferase assays indicated that GABARAPL1 represses Wnt/ß-catenin signaling stimulated by Wnt1, Dvl2 and ß-catenin. We further demonstrated that GABARAPL1 mediates degradation of Dvl2 and the effect is blocked by addition of 3-MA, a specific inhibitor of autophagy. Finally, we provided evidence that over-expression of GABARAPL1 inhibits proliferation and tumor growth of MCF7 cells in vitro and in nude mice. Taken together, our results suggested that GABARAPL1 as a tumor repressor inhibits Wnt signaling via mediating Dvl2 degradation through the autophagy pathway.