Jia-Cheng Lou

Long non-coding RNA AC023115.3 suppresses chemoresistance of glioblastoma by reducing autophagy

Malignant glioma is an aggressive brain cancer that responds poorly to chemotherapy. However, the molecular mechanism underlying the development of chemoresistance in glioma is not well-understood. In this study, we show that long non-coding RNA AC023115.3 is induced by cisplatin in human glioblastoma cells and that elevated AC023115.3 promotes cisplatin-induced apoptosis by inhibiting autophagy. Further mechanistic studies revealed that AC023115.3 acts as a competing endogenous RNA for miR-26a and attenuates the inhibitory effect of miR-26a on GSK3β, a proline-directed serine-threonine kinase that promotes the degradation of Mcl1, leading to an increase in GSK3β and a decrease in autophagy. Additionally, we discovered that AC023115.3 improves chemosensitivity of glioma cells to cisplatin by regulating the miR-26a-GSK3β-Mcl1 pathway. Thus, these data indicate that the AC023115.3-miR-26a-GSK3β signalling axis plays an important role in reducing the chemoresistance of glioma.

Long non‑coding RNA MEG3 contributes to cisplatin‑induced apoptosis via inhibition of autophagy in human glioma cells

Long non-coding RNAs (lncRNAs) function as oncogenes or tumor suppressors, and are involved in mediating tumorigenesis and resistance to chemotherapy by altering the expression of genes at various levels. Accumulating evidence suggests that the maternally expressed gene 3 (MEG3) lncRNA serves an important role in a number of cancers. However, its functional role in mediating cisplatin‑induced apoptosis of glioma cells is unknown. To investigate the role of MEG3, the mRNA levels of MEG3 under cisplatin treatment were investigated by reverse transcription‑quantitative polymerase chain reaction, and the cell viability and apoptosis were examined by MTT assay, and flow cytometry analysis and western blotting, respectively. The results demonstrated that MEG3 expression levels were increased in U87 cells following cisplatin treatment. Elevated MEG3 by lentiviral transfection enhanced the chemosensitivity of U87 cells to cisplatin, whereas knockdown of MEG3 expression by small interfering RNA transfection increased the resistance of U87 cells to cisplatin. Subsequent mechanistic studies revealed that MEG3 eliminated autophagy induced by cisplatin. Decreased MEG3‑induced autophagy improved the chemosensitivity of U87 cells to cisplatin. The results present a novel therapeutic strategy for the treatment of patients with glioblastoma multiforme.

The potential roles of aquaporin 4 in malignant gliomas

Aquaporin 4 (AQP4) is the major water channel expressed in the central nervous system and is primarily expressed in astrocytes. Recently, accumulated evidence has pointed to AQP4 as a key molecule that could play a critical role in glioma development. Discoveries of the role of AQP4 in cell migration suggest that AQP4 could be a significant factor regarding glioma malignancies. However, the AQP4 expression levels in glioma have not been fully elucidated; furthermore, the correlation of AQP4 expression with glioma malignancy remains controversial. Here, we review the expression pattern and predictive significance of AQP4 in malignant glioma. The molecular mechanism of AQP4 as it pertains to the migration and invasion of human glioma cells has been summarized. In addition, the important roles of AQP4 in combating drug resistance as well as potential pharmacological blockers of AQP4 have been systematically discussed. More research should be conducted to elucidate the potential roles of AQP4 in malignant glioma for identifying the tumor type, progression stages and optimal treatment strategies. The observed experimental results strongly emphasize the importance of this topic for future investigations.

The potential roles of dopamine in malignant glioma

Despite the numerous promising discoveries in contemporary cancer research and the emerging innovative cancer treatment strategies, the global burden of malignant glioma is expected to increase, partially due to its poor prognosis and human aging. Dopamine, a monoamine catecholamine neurotransmitter, is currently regarded as an important endogenous regulator of tumor growth. Dopamine may be an important treatment for brain tumors and could impact the pathogenesis of glioma by regulating tumor angiogenesis and vasculogenesis. Additionally, dopamine might exert an anti-glioma, cytotoxic effect by modulating apoptosis and autophagy. Dopamine and its receptors are also known to influence the immune system, as it is related to the pathogenesis of glioma. Dopamine may also increase the efficacy of anti-cancer drugs. Here, we review the potential roles of dopamine in malignant glioma and further identify the previously unknown function of dopamine as a potent regulator in the pathogenesis of glioma. Currently, the precise mechanisms regarding the protective effect of dopamine on glioma are poorly understood. However, our experimental results strongly emphasize the importance of this topic in future investigations.

Marinobufagenin inhibits glioma growth through sodium pump α1 subunit and ERK signaling-mediated mitochondrial apoptotic pathway

Malignant glioma is one of the most challenging central nervous system diseases to treat and has high rates of recurrence and mortality. Current therapies often fail to control tumor progression or improve patient survival. Marinobufagenin (MBG) is an endogenous mammalian cardiotonic steroid involved in sodium pump inhibition. Currently, various studies have indicated the potential of MBG in cancer treatments; however, the precise mechanisms are poorly understood. The functions of MBG were examined using colony formation, migration, cell cycle, and apoptosis assays in glioma cells. A mitochondrial membrane potential assay was performed to determine the mitochondrial transmembrane potential change, and cytochrome c release from mitochondria was assayed by fluorescence microscopy. An immunofluorescence assay was performed, and the nuclear translocation of NF‐κB in glioma cells was confirmed by confocal microscopy. Western blotting and RT‐qPCR were used to detect the protein and gene expression levels, respectively. In addition, transfection experiment of ATP1A1‐siRNA was further carried out to confirm the role of sodium pump α1 subunit in the anticancer effect of MBG in human glioma. The apoptosis‐promoting and anti‐inflammatory effects of MBG were further investigated, and the sodium pump α1 subunit and the ERK signaling pathway were found to be involved in the anticancer effect of MBG. The in vivo anticancer efficacy of MBG was also tested in xenografts in nude mice. Thus, therapies targeting the ERK signaling‐mediated mitochondrial apoptotic pathways regulated by MBG might represent potential treatments for human glioma, and this study could accelerate the finding of newer therapeutic approaches for malignant glioma treatment.

Bufalin inhibits glioblastoma growth by promoting proteasomal degradation of the Na+/K+-ATPase α1 subunit

Chansu is a traditional Chinese medicine that is generally recognized as a specific inhibitor of Na+/K+-ATPase. Bufalin, an active component of Chansu, is an endogenous steroid hormone with great potential as a cancer treatment. However, the mechanism by which it exerts its antitumor activity requires further research. Currently, the α1 subunit of Na+/K+-ATPase (ATP1A1) is known to exert important roles in tumorigenesis, and the precise mechanisms underlying the effect of Bufalin on the Na+/K+-ATPase α1 subunit was therefore investigated in this study to determine its role in glioblastoma treatments. The effect of ATP1A1 on the sensitivity of glioblastoma cells to Bufalin was investigated using MTT assays, RT-PCR and siRNA. Western blot was also used to explore the important roles of the ubiquitin-proteasome pathway in the Bufalin-mediated inhibition of ATP1A1. Xenografted mice were used to examine the anti-tumor activity of Bufalin in vivo. LC-MS/MS analysis was performed to determine the ability of Bufalin to traverse the blood-brain barrier (BBB). The results indicated that Bufalin inhibited the expression of ATP1A1 in glioblastoma by promoting the activation of proteasomes and the subsequent protein degradation of ATP1A1, while Bufalin had no effect on ATP1A1 protein synthesis. Bufalin also inhibited the expression of ATP1A1 in xenografted mice and significantly suppressed tumor growth. These data should contribute to future basic and clinical investigations of Bufalin. In conclusion, Bufalin significantly inhibited the expression of ATP1A1 in glioblastoma cells by activating the ubiquitin-proteasome signaling pathway. Bufalin may therefore have the potential to be an effective anti-glioma drug for human glioblastoma in the future.

Update on the therapeutic significance of estrogen receptor beta in malignant gliomas

Malignant glioma is the most fatal of the astrocytic lineage tumors despite therapeutic advances. Men have a higher glioma incidence than women, indicating that estrogen level differences between men and women may influence glioma pathogenesis. However, the mechanism underlying the anticancer effects of estrogen has not been fully clarified and is complicated by the presence of several distinct estrogen receptor types and the identification of a growing number of estrogen receptor splice variants. Specifically, it is generally accepted that estrogen receptor alpha (ERα) functions as a tumor promoter, while estrogen receptor beta (ERβ) functions as a tumor suppressor, and the role and therapeutic significance of ERβ signaling in gliomas remains elusive. Thus, a deeper analysis of ERβ could elucidate the role of estrogens in gender-related cancer incidence. ERβ has been found to be involved in complex interactions with malignant gliomas. In addition, the prognostic value of ERβ expression in glioma patients should not be ignored when considering translating experimental findings to clinical practice. More importantly, several potential drugs consisting of selective ERβ agonists have exhibited anti-glioma activities and could further extend the therapeutic potential of ERβ-selective agonists. Here, we review the literature to clarify the anti-glioma effect of ERβ. To clarify ERβ-mediated treatment effects in malignant gliomas, this review focuses on the potential mechanisms mediated by ERβ in the intracellular signaling events in glioma cells, the prognostic value of ERβ expression in glioma patients, and various ERβ agonists that could be potential drugs with anti-glioma activities.

Silencing NUDT21 Attenuates the Mesenchymal Identity of Glioblastoma Cells via the NF-κB Pathway

The proneural (PN) and mesenchymal (MES) subtypes of glioblastoma multiforme (GBM) are robust and generally consistent with classification schemes. GBMs in the MES subclass are predominantly primary tumors that, compared to PN tumors, exhibit a worse prognosis; thus, understanding the mechanism of MES differentiation may be of great benefit for the treatment of GBM. Nuclear factor kappa B (NF-κB) signaling is critically important in GBM, and activation of NF-κB could induce MES transdifferentiation in GBM, which warrants additional research. NUDT21 is a newly discovered tumor-associated gene according to our current research. The exact roles of NUDT21 in cancer incidence have not been elucidated. Here, we report that NUDT21 expression was upregulated in human glioma tissues and that NUDT21 promoted glioma cell proliferation, likely through the NF-κB signaling pathway. Gene set enrichment analysis, western blotting, and quantitative real-time reverse transcription polymerase chain reaction confirmed that NF-κB inhibitor zeta (NFKBIZ) was a downstream target affected by NUDT21 and that the MES identity genes in glioblastoma cells, CHI3L1 and FN1, were also differentially regulated. Our results suggest that NUDT21 is an upstream regulator of the NF-κB pathway and a potential molecular target for the MES subtype of GBM.

Oculomotor Paralysis, Postorbital Pain, and Hypopituitarism as First Presentations of Metastatic Gastric Cancer in the Pituitary Flourished by Internal Carotid Aneurysm: A Case Report.

AbstractMetastatic gastric cancer in the pituitary (MGCP) is rare. Few are known on the clinical and radiological characteristics of MGCP. To date, the coexistence of metastatic pituitary tumors and intracranial aneurysms has not been reported in literatures.We present a case of MGCP with internal carotid aneurysm in a 57-year-old woman, who presented with oculomotor paralysis, postorbital pain, and hypopituitarism as onset symptoms. The patient had a history of the surgical removal of gastric cancer. Magnetic resonance imaging and single-photon emission computed tomography revealed a recurrent sellar mass with intracranial and multiple bone metastases. The patient underwent subtotal removal of the tumor, followed by conformal radiotherapy and chemotherapy. Ten months after surgery, the patient died due to deterioration of her overall condition.We also reviewed and analyzed the clinical data, imaging features, and treatment methods of additional 4 cases with MGCP, which were reported in literatures. This study provides important clinical information for the diagnosis and treatment of MGCP.

Update on the effect of exogenous hormone use on glioma risk in women: a meta-analysis of case-control and cohort studies

Various studies have confirmed the important roles of endogenous hormones in the development of gliomas, while the roles of exogenous hormones remain controversial. Based on case-control studies and cohort studies, a meta-analysis was exerted to explore the effect of two exogenous hormones use (HRT: hormone replacement therapy; OC: oral contraceptives) on glioma risk. 16 eligible studies, including 11 case-control studies and 5 cohort studies, containing 8055027 women, were included in our study. All included studies have reported the relative risks (RRs) or odds ratios (ORs), and 95% confidence intervals (CIs). We use the fixed-effects model to calculate the estimated overall risk. In case-control studies, the risk of glioma was lower in women who had ever been treated with an exogenous hormone than in the control group (HRT: OR 0.91, 95% CI 0.84–0.99; OC: OR 0.99, 95% CI 0.91–1.07). In research of cohort studies, similar results have been obtained (HRT: RR 0.95, 95% CI 0.83–1.08; OC: RR 0.75, 95% CI 0.66–0.84). Our study further confirmed that the use of exogenous hormones has an important impact on the risk of glioma in women. However, more prospective studies are needed to further confirm this conclusion.