TPD52L2 impacts proliferation, invasiveness and apoptosis of glioblastoma cells via modulation of wnt/ß-catenin/snail signaling.

Intratumoral heterogeneity greatly hinders efficiency of target therapy in glioblastoma (GBM). To decipher the underlying mechanisms of heterogeneity, patient-derived adult GBM cells were separately isolated from margins of T1 gadolinium enhancing tumor lesions (PNCs) and T1 gadolinium enhancing core lesions (ECs). Single clone culture was conducted in ECs and U87MG cell line to screen clones with distinct biological phenotypes. Single cell clones with diverse phenotypes were simultaneously separated from ECs and U87 cell line. PNCs, GCs(H) and U87(H) exhibited longer cellular protrusion than ECs, GCs(L) and U87(L), respectively. Cell strains with longer protrusion exhibited higher invasive ability and lower sensitivity to temozolomide (TMZ) and radiation. Subsequently, TPD52L2 was verified as the functional protein to regulate the cellular heterogeneity by the proteomics analysis. Downregulation of TPD52L2 enhanced cell invasion whereas inhibited cell proliferation rate and sensitivity to chemotherapy in vivo and in vitro, this condition was reversed when TPD52L2 was overexpressed. The invasiveness was facilitated by up-regulating CTNNB1/ß-catenin and SNAI1/Snail mediated EMT process. In addition, the clinical data of 88 GBM cases in our neurosurgery center was analyzed to reveal the influence of TPD52L2 in the prognosis of GBM. Low expression of TPD52L2 exacerbated prognosis of GBM patients received standard radiotherapy plus concomitant and adjuvant TMZ (Stupp strategy). Taken together, TPD52L2 is an important biomarker influencing GBM prognosis.

MiR-519a functions as a tumor suppressor in glioma by targeting the oncogenic STAT3 pathway.

Glioblastoma (GBM) is among the most aggressive primary brain tumors, with a median survival rate of 12-15 months. MicroRNAs have been implicated in GBM development as oncogenes or tumor suppressors. In this study, we demonstrated that miR-519a expression was frequently downregulated in GBM specimens and cell lines, and that low-levels miR-519a expression significantly correlated with poor outcomes associated with GBM. Analysis of The Cancer Genome Atlas also demonstrated that low miR-519a expression can predict poor clinical outcomes in classical and proneural GBM subtypes. Functionally, re-expression of miR-519a effectively reduced GBM cell proliferation, migration, and invasion. Mechanistically, we confirmed that the signal transducer and activator of transcription 3 (STAT3) 3'-UTR was a putative target of miR-519a, and that re-expression of STAT3 abrogated miR-519a function in GBM cells. Furthermore, we found that STAT3 expression negatively correlated with that of miR-519a in human GBM tissues. These results elucidated the prognostic value and tumor-suppressor role of miR-519a in GBM and further suggested it as a potential therapeutic target for GBM treatment.

Does the calcification of adamantinomatous craniopharyngioma resemble the calcium deposition of osteogenesis/odontogenesis?

AIMS: Calcification in adamantinomatous craniopharyngioma (ACP) is troublesome for surgical intervention. The aim of this study was to examine the osteogenic proteins that play important roles in the calcium deposition of the odontogenic/osteogenic tissues in craniopharyngioma. METHODS AND RESULTS: Craniopharyngiomas (n = 89) were investigated for the presence and expression pattern of the osteoinductive/odontoinductive factor bone morphogenetic protein-2 (Bmp2) and two osteoblastic differentiation makers, Runt-related transcription factor-2 (Runx2) and Osterix, using immunohistochemistry and Western blotting. Our results showed that Bmp2, Runx2 and Osterix levels increased in cases with high calcification and correlated positively with the degree of calcification in ACP, whereas they showed little or no expression in squamous papillary craniopharyngioma. In ACP, Bmp2 was expressed primarily in the stellate reticulum and whorl-like array cells; Runx2 and Osterix tended to be expressed in calcification-related epithelia, including whorl-like array cells and epithelia in/around wet keratin and calcification lesions. CONCLUSIONS: Our study indicated, for the first time, that osteogenic factor Bmp2 may play an important role in the calcification of ACP via autocrine or paracrine mechanisms. Given the presence of osteogenic markers (Runx2 and Osterix), craniopharyngioma cells could differentiate into an osteoblast-like lineage, and the process of craniopharyngioma calcification resembles that which occurs in osteogenesis/odontogenesis.

Calretinin is expressed in the stroma of adamantinomatous craniopharyngioma and may induce calcification.

OBJECTIVES: Calretinin is expressed in many tumors. However, the role of calretinin in craniopharyngiomas (CPs) remains unknown. PATIENTS AND METHODS: The study included 77 adamantinomatous CP (ACP). ACP calcification was divided into several categories on the basis of the incidence and extent of the calcium deposits evident on computed tomography (CT) images. The presence and expression pattern of calretinin were investigated using immunohistochemistry and western blotting. CP cell culture and small interfering (si)RNA of calretinin transfection was also carried out to clarify the role of calretinin in ACP calcification. RESULTS: 61 cases exhibited calcification on CT, and 63 samples were immunopositive to calretinin. The western blotting results were consistent with the immunohistochemical findings. Calretinin expressions differed significantly among ACP groups basing on calcification degree, and a positive correlation was observed between calretinin expression and calcification degree (r=0.853, P<0.001). Calretinin siRNA transfection further demonstrated the role calretinin played in ACP calcification. CONCLUSIONS: Calretinin is expressed in the tumor stoma of calcified ACP, and its expression correlated with calcification degree. Drugs that target calretinin to reduce calcification and improve the postoperative function of ACP patients should be further researched.

Association between the XRCC1 Arg399Gln polymorphism and risk of cancer: evidence from 297 case-control studies.

BACKGROUND: The Arg399Gln polymorphism in the X-ray cross-complementing group 1 (XRCC1) had been implicated in cancer susceptibility. The previous published data on the association between XRCC1 Arg399Gln polymorphism and cancer risk remained controversial. METHODOLOGY/PRINCIPAL FINDINGS: To derive a more precise estimation of the association between the XRCC1 Arg399Gln polymorphism and overall cancer risk, we performed a meta-analysis of 297 case-control studies, in which a total of 93,941 cases and 121,480 controls were included. Overall, significantly increased cancer risk was observed in any genetic model (dominant model: odds ration [OR] = 1.04, 95% confidence interval [CI] = 1.01-1.07; recessive model: OR = 1.08, 95% CI = 1.03-1.13; additive model: OR = 1.09, 95% CI = 1.04-1.14) when all eligible studies were pooled into the meta-analysis. In further stratified and sensitivity analyses, significantly elevated hepatocellular and breast cancers risk were observed in Asians (dominant model: OR = 1.39, 95% CI = 1.06-1.84) and in Indians (dominant model: OR = 1.64, 95% CI = 1.31-2.04; recessive model: OR = 1.94, 95% CI = 1.09-3.47; additive model: OR = 2.06, 95% CI = 1.50-2.84), respectively. CONCLUSIONS/SIGNIFICANCE: This meta-analysis suggests the participation of XRCC1 Arg399Gln is a genetic susceptibility for hepatocellular cancer in Asians and breast cancer in Indians. Moreover, our work also points out the importance of new studies for Arg399Gln association in some cancer types, such as glioma, gastric cancer, and oral cancer, where at least some of the covariates responsible for heterogeneity could be controlled, to obtain a more conclusive understanding about the function of the XRCC1 Arg399Gln polymorphism in cancer development.

The arachnoid sleeve enveloping the pituitary stalk: anatomical and histologic study.

BACKGROUND: The arachnoid membrane in the suprasellar region may affect the growth pattern of sellar and suprasellar tumors however, the topographic relationships between the pituitary stalk and the surrounding arachnoid membranes remained unclear. OBJECTIVE: The aim of this study was to evaluate the anatomical and histological characteristics of the arachnoid membranes. METHODS: Microsurgical dissection and anatomical observation were performed in 16 formalin-fixed adult cadaver heads. In the other 5 adult cadaver heads, histologic sections of sellar-suprasellar specimens were studied under light microscopy. RESULTS: An arachnoid sleeve enveloping the pituitary stalk of variable length presented in all specimens, which was formed by direct upward extension of the basal arachnoid membrane covering the diaphragma sellae. In the majority of specimens, the arachnoid sleeve was reinforced by the arachnoid trabeculae originating from the basal arachnoid membrane, the Liliequist membrane, and the medial carotid membrane. CONCLUSION: The relationship between the pituitary stalk and the surrounding arachnoid membrane is important in evaluating the growth patterns of the sellar and suprasellar tumors, and their topographical relationships.