Qi Pang

c-Met expression is associated with time to recurrence in patients with glioblastoma multiforme

The aim of this study was to explore the difference in c-Met expression between primary and recurrent glioblastoma multiforme (GBM), and to determine whether the dysregulation of c-Met expression has a role in the malignant progression of GBM. Paired primary and recurrent GBM specimens from the same patient were evaluated using immunohistochemical analysis. The association between c-Met expression and progression-free survival time (PFST) was analyzed. There was a significant difference in c-Met expression between primary and recurrent tumors (p=0.020), and patients with tumors expressing c-Met at a higher level had a significantly shorter PFST (6.1 months vs. 11.5 months; p=0.026). Our study indicates that recurrent GBM express c-Met at a higher level and that c-Met overexpression is associated with shorter PFST in patients with GBM. These findings suggest that c-Met potentially has an important role in the treatment of GBM.

Surgical outcomes and prognostic factors of transsphenoidal surgery for prolactinoma in men: a single-center experience with 87 consecutive cases

Context Little systematic data on male prolactinomas treated with surgery are available. Objective To clarify the clinical features and confirm the efficacy of transsphenoidal surgery for male prolactinomas and predictive factors after initial surgery. Patients and methods This retrospective study included 87 male patients with prolactinoma treated by transsphenoidal surgery at an academic medical center. Hormonal and visual status, remission rates, and the rate of tumor relapse, as well as predictive factors, were evaluated. Results Postoperative initial remission was achieved in 52.9% of patients. The remission rate was markedly higher in microadenomas (83.3%) than in macroadenomas (44.9%). Logistic regression analysis showed that the predictive factors of the early negative outcomes were high preoperative prolactin (PRL) levels and tumor invasion. After a median follow-up of 45 months, the long-term remission rate was 42.5%, and relapse of hyperprolactinemia occurred in 19.6% of the cured patients. The 5-year recurrence-free survival was 78.2% (95% confidence interval, 62.3-88.1%). When surgery was followed by adjuvant treatment in uncured and recurrent patients, 78.8% of patients in the entire group in the absence of dopamine agonists obtained biochemical remission at the end of follow-up. Conclusion Transsphenoidal surgery is a viable treatment alternative for male prolactinomas. The remission rates of male patients with microadenomas and/or intrasellar macroprolactinomas by surgery alone remain excellent, and surgery followed by adjuvant therapy as necessary is required for optimizing management of male prolactinomas, especially for extrasellar macroprolactinomas. The early negative results are associated with preoperative PRL levels and tumor invasion.

Expression of high-mobility group AT-hook protein 2 and its prognostic significance in malignant gliomas

High-mobility group AT-hook protein 2 (HMGA2) is an architectural transcription factor associated with malignancy, invasiveness, and poor prognosis in a variety of human neoplasms. This study investigated HMGA2 expression and prognostic value in human gliomas. We also correlated HMGA2 expression with Ki-67 labeling index and matrix metalloproteinase-2. Expression of HMGA2 in 78 human gliomas and 7 human normal brain samples was studied using immunohistochemistry, and 29 gliomas were randomly selected and studied along with the normal brain by real-time quantitative polymerase chain reaction and Western blot analysis. Expression of HMGA2 protein was significantly higher in glioblastoma multiforme (World Health Organization [WHO] grade IV; P = .007) and anaplastic astrocytoma (WHO grade III; P = .037) than in diffuse astrocytoma (WHO grade II). Expression of HMGA2 correlated significantly with expression of Ki-67 (r = 0.415, P < .01) and matrix metalloproteinase-2 (r = 0.363, P < .01), but not with patient sex and age. The real-time quantitative polymerase chain reaction and Western blot analysis revealed similar results. Patients with tumors expressing HMGA2 at a higher level had a significantly shorter progression-free survival time (11.2 months versus 18.8 months; P = .021). Expression of HMGA2 significantly correlates with tumor cell proliferation, invasion, and survival in gliomas. The results suggest that HMGA2 has an important role in the treatment and prognosis of these cancers.

Polymorphism rs42524 of COL1A2 and sporadic intracranial aneurysms in the Chinese population

OBJECT The COL1A2 gene at 7q22.1 has been shown to be associated with familial intracranial aneurysms (IAs) in the Japanese population. In the present study, the authors investigated the correlation between the presence of the rs42524 polymorphism in COL1A2 and the occurrence of sporadic IAs in Chinese patients. METHODS The polymorphism rs42524 of the COL1A2 gene was identified by polymerase chain reaction-based restriction analysis in genomic DNA from 226 patients with sporadic IAs (mean age 51.49 +/- 11.47 years) and 326 control participants (mean age 52.33 +/- 10.50 years). Neurological assessments were performed using the Hunt and Hess grading system, and differences in allelic and genotypic frequencies between the patient and control groups were evaluated with the chi-square test. RESULTS There was a significant difference in either the genotype distribution (chi(2) = 11.99, p = 0.002) or allelic frequencies (chi(2) = 11.96, p = 0.001, odds ratio 2.579, 95% confidence interval 1.486-4.476) between patients with IAs and patients in the control group. CONCLUSIONS The rs42524 polymorphism of COL1A2 could be a genetic risk factor for sporadic IAs among individuals of Chinese Han ethnicity. This study is the first to confirm the association between COL1A2 and IAs.

Expression of hepatocyte growth factor and its receptor c-Met in human pituitary adenomas

Hepatocyte growth factor (HGF) and its receptor c-Met have been known as key determinants of growth and angiogenesis in some brain tumors like gliomas, meningiomas, and schwannomas. But little is known about their expression in pituitary adenomas. In this study, the expression of HGF and c-Met in pituitary adenomas of different histology types was investigated by immunohistochemistry, and correlative analysis of their expression with microvessel density (MVD), Ki-67 expression, and other clinicopathologic factors was made. The results showed that the expression of HGF and c-Met exists in 98% (64 of 65) and 92% (60 of 65) pituitary adenomas, respectively, and co-expression of them existed in 91% (59 of 65) adenomas. HGF had significant correlation with MVD (Spearmans correlation coefficient, r = .31, P = .01) and Ki-67 (r = .32, P = .01). c-Met had significant correlation with MVD (r = .30, P = .02) and Ki-67 (r = .38, P = .00). HGF and c-Met expression had no significant correlation with age or extrasellar extension. There were no significant differences in HGF and c-Met expression between pituitary adenomas of different histology types. The results indicate that HGF and c-Met are widely expressed in pituitary adenomas, and their expression correlates with MVD and Ki-67 expression.

The different HMGA1 expression of total population of glioblastoma cell line U251 and glioma stem cells isolated from U251

The high-mobility group A1 (HMGA1) protein is a non-histone architectural nuclear factor and participates in diverse biological processes, including gene transcription, embryogenesis, cell cycle regulation, apoptosis, and even neoplastic transformation. In our study, glioma stem cells (GSCs) expressing the surface marker CD133 from human glioblastoma cell line U251 were isolated using MACS column and were analyzed using immunofluorescence and flow cytometry (FCM). The different expression of HMGA1 was detected using real-time RT-PCR and Western blot at transcriptional and translational levels between U251 and isolated GSCs. The results show that GSCs were successfully isolated from U251 and cultured in serum-free medium (SMF). The percentage of GSCs in U251 was 0.32%±0.07%. HMGA1 expression was significantly higher in GSCs than in glioblastoma cells (P<0.05), up to 6.13±0.25-fold and 2.75±0.99-fold at transcriptional and translational levels, respectively. These results indicated HMGA1 is overexpressed in GSCs as compared to glioblastoma cell line U251, which points to the expression of HMGA1 being closely related to malignant proliferation, invasion, and differentiation of tumors from the prospective of tumor stem cells (TSCs). We conclude that HMGA1 may be a potential biomarker and rational therapeutic target for glioblastoma and GSC.

Polymorphism rs4934 of SERPINA3 and Sporadic Intracranial Aneurysms in the Chinese Population

Background: Serine protease inhibitor member 3 of clade A (SERPINA3) has been shown as a risk factor for aneurysmal subarachnoid hemorrhage in a Polish population. In the present study, the authors investigated the correlation between the rs4934 polymorphism of SERPINA3 and sporadic intracranial aneurysms in Chinese patients. Methods: The rs4934 polymorphism of SERPINA3 was identified by PCR and Taqman MGB probe analysis in genomic DNA from 275 patients with sporadic intracranial aneurysms (mean age 50.83 ± 10.78 years) and 361 control participants (mean age 53.21 ± 10.81 years). Differences in allelic and genotypic frequencies between the patient and control groups were evaluated with the χ2 test. Results: No significant difference was found in either the genotype distribution or allelic frequencies of SERPINA3 between patients and controls. Conclusions: The rs4934 polymorphism of SERPINA3 is not associated with sporadic intracranial aneurysms among individuals of Chinese Han ethnicity.

LncRNA HSP90AA1-IT1 promotes gliomas by targeting miR-885-5p-CDK2 pathway

It is well established that ncRNAs are emerging as important regulators in various types of cancers, however, their functions and contributions in cancers remain insufficiently defined. In this study, we reported the expression levels of a long noncoding RNA (lncRNA), named HSP90AA1-IT1 (HSP90AA1 intronic transcript 1), appeared to correlate with the pathological grades of gliomas and high level of HSP90AA1-IT1 indicated poor prognosis. Downregulation of HSP90AA1-IT1 in the glioma cell lines significantly suppressed cell viability, proliferation, EMT, invasion and migration in addition to an increase in apoptosis and aberrant cell cycle progression. The tumorigenic capacity of these cells in vivo were also inhibited. We further demonstrated that the oncogenic effects of HSP90AA1-IT1 could be mediated by a direct binding to miR-885-5p. Sharing the same binding sites with CDK2, a key regulator in gliomagenesis, HSP90AA1-IT1 competitively bound to miR-885-5p, thereby prevented CDK2 from miR-885-5p mediated post-transcriptional repression. Taken together, it is concluded that HSP90AA1-IT1, performs its function via regulating the development of gliomas through miR-885-5p-CDK2 signaling axis, and this has added new perspective to its role in tumorigenesis, thus providing potential therapeutic targets for glioma treatment.

Melatonin Inhibits Glioblastoma Stem-like cells through Suppression of EZH2-NOTCH1 Signaling Axis.

Glioblastoma stem-like cells (GSCs) play essential roles in glioma growth, radio- and chemo-resistance, and recurrence. Elimination of GSCs has therefore become a key strategy and challenge in glioblastoma therapy. Here, we show that melatonin, an indolamine derived from I-tryptophan, significantly inhibited viability and self-renewal ability of GSCs accompanied by a decrease of stem cell markers. We have identified EZH2-NOTCH1 signaling as the key signal pathway that regulated the effects of melatonin in the GSCs. Instead of transcriptionally silencing gene expression by generating a methylated epigenetic mark at histone 3 at lysine 27 (H3K27), EZH2 regulates NOTCH1 expression by directly binding to the NOTCH1 promoter. Moreover, correlation between the expressions of EZH2 and NOTCH intracellular domain 1 (NICD1) was observed in the clinical tumor samples, evidently supporting the existence of EZH2-NOTCH1 interaction in the gliomas and GSCs. Collectively, we demonstrated that melatonin, a potential tumor inhibitor, performs its function partly by suppressing GSC properties through EZH2-NOTCH1 signaling axis.

EZH2 promotes metabolic reprogramming in glioblastomas through epigenetic repression of EAF2-HIF1α signaling

Cancer cells prefer glycolysis for energy metabolism, even when there is sufficient oxygen to make it unnecessary. This is called the Warburg effect, and it promotes tumorigenesis and malignant progression. In this study, we demonstrated that EZH2, a multifaceted oncogenic protein involved in tumor proliferation, invasion and metastasis, promotes glioblastoma tumorigenesis and malignant progression through activation of the Warburg effect. We observed that HIF1α is a target of EZH2 whose activation is necessary for EZH2-mediated metabolic adaption, and that HIF1α is activated upon EZH2 overexpression. EZH2 suppressed expression of EAF2, which in turn upregulated HIF1α levels. We conclude from these results that EZH2 promotes tumorigenesis and malignant progression in part by activating glycolysis through an EAF2-HIF1α signaling axis.