PLPP2: Potential therapeutic target of breast cancer in PLPP family.

PLPPs (Phospholipid phosphatases) are widely expressed in different human tissues, regulate cell signal transduction, and are overexpressed in cancers such as gliomas, pancreatic adenocarcinoma, lung adenocarcinoma, and so on. As a member of the PLPP family, PLPP2 (phospholipid phosphatase 2) plays a vital role in the occurrence and development of breast cancer, but its mechanism is still unclear. Our research found that PLPP2 was overexpressed in breast cancer, and the higher expression level of PLPP2 showed a worse prognosis for breast cancer patients. Further analysis showed that overexpression of PLPP2 affected the expression of CDC34 (cell-division cycle 34), LSM7 (Like-Smith 7), and SGTA (small glutamine-rich tetratricopeptide repeat-containing protein alpha) through EMT (epigenetic-mesenchymal transition) related pathways to promote the occurrence and development of breast cancer. In vitro, silencing PLPP2 significantly reduced the proliferation, invasion, and migration abilities of human breast cancer cells MDA-MB-231. ER+ is a common subtype of breast cancer. Furthermore, we found that the overexpression of PLPP2 was significantly related to the poor prognosis of ER+ breast cancer. These results indicate that PLPP2 has value as a potential therapeutic target for breast cancer, especially for ER+ breast cancer.

ADAMDEC1 accelerates GBM progression via activation of the MMP2-related pathway.

The ADAM (a disintegrin and metalloprotease) gene-related family including ADAM, ADAMTS, and ADAM-like decysin-1 has been reported to play an important role in the pathogenesis of multiple diseases, including cancers (lung cancer, gliomas, colorectal cancer, and gastrointestinal cancer). However, its biological role in gliomas remains largely unknown. Here, we aimed to investigate the biological functions and potential mechanism of ADAMDEC1 in gliomas. The mRNA and protein expression levels of ADAMDEC1 were upregulated in glioma tissues and cell lines. ADAMDEC1 showed a phenomenon of "abundance and disappear" expression in gliomas and normal tissues in that the higher the expression of ADAMDEC1 presented, the higher the malignancy of gliomas and the worse the prognosis. High expression of ADAMDEC1 was associated with immune response. Knockdown of ADAMDEC1 could decrease the proliferation and colony-forming ability of LN229 cells, whereas ADAMDEC1 overexpression has opposite effects in LN229 cells in vitro. Furthermore, we identified that ADAMDEC1 accelerates GBM progression via the activation of the MMP2 pathway. In the present study, we found that the expression levels of ADAMDEC1 were significantly elevated compared with other ADAMs by analyzing the expression levels of ADAM family proteins in gliomas. This suggests that ADAMDEC1 has potential as a glioma clinical marker and immunotherapy target.

Role of TRPV1 ion channel in cervical squamous cell carcinoma genesis.

The transient receptor potential (TRP) family is a widely expressed superfamily of ion channels that regulate intracellular Ca2+ homeostasis and signal transduction. Abnormal expression of TRPV1 is closely related to malignant tumors of the female reproductive system such as breast, ovarian, cervical and endometrial cancers. In this study, we found a significant reduction of TRPV1 expression in cervical squamous cell carcinoma and this expression is inversely association with the risk of cervical squamous cell carcinoma. Furthermore, TRPV1 is involved in cell differentiation, iron death, inflammatory response, and metabolic regulation in cervical squamous cell carcinoma. Meanwhile TRPV1 is positively correlated with T cells and negatively associated with macrophages, indicating that TRPV is associated with tumor cell immunity. Therefore, TRPV1 may be a potential marker of cervical cancer and a promising anti-cancer drug candidate.

Hormone supply to the pituitary gland: A comprehensive investigation of female­related tumors (Review).

The hypothalamus acts on the pituitary gland after signal integration, thus regulating various physiological functions of the body. The pituitary gland includes the adenohypophysis and neurohypophysis, which differ in structure and function. The hypothalamus­hypophysis axis controls the secretion of adenohypophyseal hormones through the pituitary portal vein system. Thyroid­stimulating hormone, adrenocorticotropic hormone, gonadotropin, growth hormone (GH), and prolactin (PRL) are secreted by the adenohypophysis and regulate the functions of the body in physiological and pathological conditions. The aim of this review was to summarize the functions of female­associated hormones (GH, PRL, luteinizing hormone, and follicle­stimulating hormone) in tumors. Their pathophysiology was described and the mechanisms underlying female hormone­related diseases were investigated.

Two new species of Steccherinum (Polyporales, Basidiomycota) from southern China based on morphology and DNA sequence data.

Two new wood-inhabiting fungal species, Steccherinum hirsutum and S. yunnanense spp. nov., are proposed based on a combination of morphological features and molecular evidence. Sequences of internal transcribed spacer and large subunit region of nuculear ribosomal RNA gene of the studied samples were generated, and phylogenetic analyses were performed using maximum likelihood, maximum parsimony and bayesian inference methods. Steccherinum hirsutum is characterized by an annual growth habit, stipitate basidiocarps with scarlet to red, odontioid hymenial surface, a dimitic hyphal system with clamped generative hyphae negative in Melzer's reaction, and acyanophilous basidiospores measuring 2.5-3.5 × 1.5-2.5 µm. Steccherinum yunnanense is distinguished by resupinate basidiomata with odontioid hymenial surface, a dimitic hyphal system with clamped generative hyphae, strongly encrusted cystidia and ellipsoid, hyaline, thin-walled, smooth basidiospores (3.5-4.5 × 2-3.5 µm). The phylogenetic analyses comfirmed that two new species nest in Steccherinum, in the residual polyporoid clade.

A phylogenetic and taxonomic study on Steccherinum (Polyporales, Basidiomycota): Focusing on three new Steccherinum species from southern China.

The wood-inhabiting fungi play an integral role in wood degradation and the cycle of matter in the ecological system. They are considered as the "key player" in wood decomposition, because of their ability to produce all kinds of enzymes that break down woody lignin, cellulose and hemicellulose. In the present study, three new wood-inhabiting fungal species, Steccherinum fissurutum, S. punctatum and S. subtropicum spp. nov., collected from southern China, are proposed based on a combination of morphological features and molecular evidence. Steccherinum fissurutum is characterized by the resupinate, subceraceous basidiomata with cracked hymenophore, a monomitic hyphal system with clamped generative hyphae and cylindrical basidiospores; S. punctatum is characterized by the annual, punctate basidiomata with leathery hymenophore, cylindrical, strongly encrusted cystidia and ellipsoid basidiospores (3.6-4.5 ×2.6-3.4 µm); S. subtropicum is characterized by its effuse-reflexed basidiomata, a odontioid hymenophore with pink to lilac hymenial surface and ellipsoid basidiospores measuring as (2.8-3.4 × 2.0-2.7 µm). Sequences of ITS and nLSU rRNA markers of the studied samples were generated, and phylogenetic analyses were performed with maximum likelihood, maximum parsimony, and Bayesian inference methods. The ITS+nLSU analysis of the family Steccherinaceae indicated that the three new species clustered into the genus Steccherinum. Based on further analysis of ITS+nLSU dataset, the phylogenetic analysis confirmed that S. subtropicum was sister to S. enuispinum; S. fissurutum formed a monophyletic lineage; S. punctatum grouped with a clade comprised S. straminellum and S. ciliolatum.

Phospholipid Phosphatase 4 as a Driver of Malignant Glioma and Pancreatic Adenocarcinoma.

Glioma and pancreatic cancer are tumors with a high degree of malignancy, morbidity, and mortality. The present study explored possible molecular mechanisms and potential diagnostic and prognostic biomarker-PLPP4 of glioma and PAAD. PLPP4 is differentially elevated in glioma and PAAD tissues. Statistical analysis from TCGA demonstrated that high expression of PLPP4 significantly and positively correlated with clinicopathological features, including pathological grade and poor overall survival in glioma and PAAD patients. Following this, the methylation levels of PLPP4 also affected overall survival in clinical tissue samples. Silencing PLPP4 inhibited proliferation, invasion, and migration in LN229 cells and PANC-1 cells. Moreover, the combination of multiple proteins for the prognosis prediction of glioma and PAAD was evaluated. These results were conducted to elaborate on the potential roles of the biomarker-PLPP4 in clonability and invasion of glioma and PAAD cells.

Curcumin inhibits adverse psychological stress-induced proliferation and invasion of glioma cells via down-regulating the ERK/MAPK pathway.

Curcumin is a natural polyphenol extracted from the rhizome of Curcuma that has an important antitumour effect, but its effect on adverse psychological stress-induced tumour proliferation and invasion has not been reported to date. Here, we found that curcumin not only inhibited the growth of xenografts in chronically stressed nude mice, but also decreased the expression of matrix metalloproteinase (MMP)-2/9 and CD147 in tumour tissues. Exogenous norepinephrine (NE) was used to stimulate glioma cells to simulate the stress environment in vitro, and it was found that curcumin inhibited the NE-induced proliferation and invasion of glioma cells in a dose-dependent manner. Further research found that the effects of NE on glioma cells could lead to the activation of the mitogen-activated protein kinase (MAPK) signalling pathway through ß-adrenergic receptor, while curcumin suppressed the level of extracellular signal-regulated kinase (ERK)1/2 phosphorylation. In addition, blocking ERK1/2 expression with U0126 resulted in the down-regulated expression of CD147, which further led to the decreased expression of MMP-2 and MMP-9. Curcumin could also inhibit the expression of cyclin D1/CDK4/6 and anti-apoptotic protein Bcl-2/Bcl-XL induced by NE, and induced cell cycle changes and increased apoptosis. Therefore, curcumin may be a potential candidate drug for preventing and treating the progression of glioma induced by adverse psychological stress.

Psychological Stress Up-Regulates CD147 Expression Through Beta-Arrestin1/ERK to Promote Proliferation and Invasiveness of Glioma Cells.

Psychological stress is closely related to the occurrence and prognosis of various malignant tumors, but the underlying mechanisms are not well studied. CD147 has been reported to be expressed in glioma and other malignant tumors. CD147 not only participates in lactic acid transport, but it also plays an important role in the invasion and metastasis of malignant tumor cells by stimulating the production of numerous matrix metalloproteinases (MMPs) and vascular endothelial growth factor by fibroblasts, and could also act as an autocrine factor stimulating MMPs production in metastatic tumor cells. Here, we found that silencing CD147 in chronically stressed nude mice not only inhibited the proliferation of xenografts but also decreased matrix metalloproteinase-2, 9 expression and lactic acid content in tumor tissues. Furthermore, norepinephrine (NE) was significantly increased in the serum of nude mice in glioma stress model. To determine the underlying cellular mechanism, we added exogenous NE into LN229 and U87 cells to simulate the stress environment in vitro. The invasiveness of the glioma cells was subsequently examined using a Matrigel invasion assay. We demonstrated that knockdown of CD147 inhibited glioma invasiveness and metastasis with norepinephrine stimulation. Luciferase reporter gene experiments further demonstrated that the expression of CD147 is up-regulated primarily by norepinephrine via the ß-Adrenalin receptor (ßAR)-ß-arrestin1-ERK1/2-Sp1 pathway. High expression of CD147 promoted the secretion of MMP-2 and the increment of lactic acid, which accelerated the augmented invasion and metastasis of glioma induced by psychological stress. Taken together, these results suggest that psychological stress promotes glioma proliferation and invasiveness by up-regulating CD147 expression. Thus, CD147 might be a potential target site in the treatment of glioma progression induced by chronic psychological stress.

Duodenal-Jejunal Bypass Ameliorates Type 2 Diabetes Mellitus by Activating Insulin Signaling and Improving Glucose Utilization in the Brain.

BACKGROUND: Duodenal-jejunal bypass (DJB) can dramatically improve type 2 diabetes independent of weight loss and food restriction. Increasing evidence has demonstrated that brain insulin signaling plays an important role in the pathophysiology of type 2 diabetes. This study explores whether the antidiabetic effect of DJB is involved in brain insulin signaling activation and brain glucose utilization. METHODS: A diabetic rat model was established by high-fat and high-glucose diet. DJB or sham surgery was performed in diabetic rats. 18F-FDG PET scanning was used to detect glucose uptake in different organs, particularly in the brain. The levels of glucose transporters, glucose utilization-related proteins (HK1 and PFK2), insulin, and insulin signaling pathway-related proteins (InsR, IRS1/2, PI3K, and p-Akt) in the brain tissues were evaluated and analyzed. RESULTS: The results showed that DJB significantly improved basal glycemic parameters and reversed the decreasing glucose uptake in the brains of type 2 diabetic rats. DJB significantly increased not only the expression levels of brain insulin, IRS1/2, PI3K, and p-Akt but also the levels of the glucose utilization enzymes HK1 and PFK2 in the brain. CONCLUSION: These results indicate that enhanced brain insulin signaling transduction and brain glucose utilization play important roles in the antidiabetic effect of DJB.

[Psychological distress promotes proliferation and invasion of glioma by upregulating lactate deoxygenase A].

Objective To investigate the role of lactate deoxygenase A (LDHA) expression in the proliferation and invasion of glioma promoted by the psychological distress. Methods The glioma-bearing nude mice were divided into tumor bearing group, stress tumor bearing group, negative control, short hairpin RNA (shRNA)-lactate dehydrogenase A (LDHA) group and shRNA-LDHA stress group. Four weeks after stress, the tumor size of each group was measured; meanwhile, norepinephrine (NE) andadrenaline (EPI) in the blood were detected by ELISA; lactic acid in the tumor tissue was determined by colorimetry. And the expression level of LDHA was detected by Western blotting. The proliferation of glioma LN229 cells stimulated by NE was detected by CCK-8 assay and plate clone formation assay; TranswellTM assay was used to test the invasive ability of LN229 cells. The level of LDHA mRNA was detected by real-time quantitative PCR. The expressions of LDHA, ERK1/2 and hypoxia-induced factor-1α (HIF-1α) were observed using Western blotting. By constructing the reporter gene, we studied the mechanism of LDHA expression regulated by NE. Results The tumor size and the levels of EPI, NE, lactic acid and LDHA in the stress group significantly increased as compared with the tumor bearing group. After silencing LDHA, the proliferation rate and lactate content decreased. Compared with the control group, the mRNA and protein levels of LDHA in NE group was significantly elevated; the phosphorylation levels of HIF-1α and ERK1/2 was significantly raised; and cell proliferation and invasion ability were also enhanced. Promoter luciferase reporter assay confirmed that NE up-regulated the expression of LDHA by HIF-1α. Conclusion Adverse psychological stress can promote the proliferation and invasion of glioma cells by upregulating LDHA expression.

Adaptive Activation of a Stress Response Pathway Improves Learning and Memory Through Gs and ß-Arrestin-1-Regulated Lactate Metabolism.

BACKGROUND: Stress is a conserved physiological response in mammals. Whereas moderate stress strengthens memory to improve reactions to previously experienced difficult situations, too much stress is harmful. METHODS: We used specific ß-adrenergic agonists, as well as ß2-adrenergic receptor (ß2AR) and arrestin knockout models, to study the effects of adaptive ß2AR activation on cognitive function using Morris water maze and object recognition experiments. We used molecular and cell biological approaches to elucidate the signaling subnetworks. RESULTS: We observed that the duration of the adaptive ß2AR activation determines its consequences on learning and memory. Short-term formoterol treatment, for 3 to 5 days, improved cognitive function; however, prolonged ß2AR activation, for more than 6 days, produced harmful effects. We identified the activation of several signaling networks downstream of ß2AR, as well as an essential role for arrestin and lactate metabolism in promoting cognitive ability. Whereas Gs-protein kinase A-cyclic adenosine monophosphate response element binding protein signaling modulated monocarboxylate transporter 1 expression, ß-arrestin-1 controlled expression levels of monocarboxylate transporter 4 and lactate dehydrogenase A through the formation of a ß-arrestin-1/phospho-mitogen-activated protein kinase/hypoxia-inducible factor-1α ternary complex to upregulate lactate metabolism in astrocyte-derived U251 cells. Conversely, long-term treatment with formoterol led to the desensitization of ß2ARs, which was responsible for its decreased beneficial effects. CONCLUSIONS: Our results not only revealed that ß-arrestin-1 regulated lactate metabolism to contribute to ß2AR functions in improved memory formation, but also indicated that the appropriate management of one specific stress pathway, such as through the clinical drug formoterol, may exert beneficial effects on cognitive abilities.

A stress response pathway in mice upregulates somatostatin level and transcription in pancreatic delta cells through Gs and ß-arrestin 1.

AIMS/HYPOTHESIS: Somatostatin secretion from islet delta cells plays an important role in regulating islet function and is tightly controlled by environmental changes. Activation of the adrenergic system promoted somatostatin secretion from islet delta cells; however, the role of the adrenergic system in regulating somatostatin content and transcription has not been defined. An imbalance between the somatostatin content and its secretion may cause dysfunctions in the islet delta cells. We have investigated the role of the adrenergic system in the modulation of somatostatin content and transcription in pancreatic delta cells and the detailed underlying mechanisms of this regulation. METHODS: The stress hormone adrenaline (epinephrine), specific adrenergic agonists or specific adrenergic antagonists were applied to islets from either wild-type or specific adrenergic receptor knockout mice and pancreatic delta cell lines to investigate their effects on somatostatin content and transcription. The GloSensor assay, quantitative real-time PCR, western blots and the dual luciferase assay were used to monitor the cAMP level, somatostatin expression, activations of kinases and transcriptional factors. Arrb1 knockout mice, specific Creb or Pax6 mutations and specific kinase inhibitors were used to dissect the signalling pathway. RESULTS: Adrenaline and isoprenaline increased somatostatin content and transcription through the activation of ß1-/ß2-adrenergic receptors (ß1-/ß2ARs). The somatostatin content in ß1AR(-/-) /ß2AR(-/-) (Adrb1/Adrb2 knockout) mice was 50% lower than in ß1AR(+/+)/ß2AR (+/+) mice. Two parallel signalling pathways, Gs-cAMP-protein kinase A (PKA)-cAMP response element binding protein (CREB) and ß-arrestin 1-extracellular signal-related kinase (ERK)-paired box protein 6 (PAX6), cooperatively regulated isoprenaline-induced somatostatin transcription. CONCLUSIONS/INTERPRETATION: A stress pathway increased somatostatin content and transcription through ß-adrenergic agonism. ß-Arrestin1, ERK and PAX6 are important pancreatic delta cell regulators in addition to cAMP, PKA and CREB. Dysfunction of ß-adrenergic agonism may impair pancreatic delta cell function.

Molecular mechanism of ERK dephosphorylation by striatal-enriched protein tyrosine phosphatase.

Striatal-enriched tyrosine phosphatase (STEP) is an important regulator of neuronal synaptic plasticity, and its abnormal level or activity contributes to cognitive disorders. One crucial downstream effector and direct substrate of STEP is extracellular signal-regulated protein kinase (ERK), which has important functions in spine stabilisation and action potential transmission. The inhibition of STEP activity toward phospho-ERK has the potential to treat neuronal diseases, but the detailed mechanism underlying the dephosphorylation of phospho-ERK by STEP is not known. Therefore, we examined STEP activity toward para-nitrophenyl phosphate, phospho-tyrosine-containing peptides, and the full-length phospho-ERK protein using STEP mutants with different structural features. STEP was found to be a highly efficient ERK tyrosine phosphatase that required both its N-terminal regulatory region and key residues in its active site. Specifically, both kinase interaction motif (KIM) and kinase-specific sequence of STEP were required for ERK interaction. In addition to the N-terminal kinase-specific sequence region, S245, hydrophobic residues L249/L251, and basic residues R242/R243 located in the KIM region were important in controlling STEP activity toward phospho-ERK. Further kinetic experiments revealed subtle structural differences between STEP and HePTP that affected the interactions of their KIMs with ERK. Moreover, STEP recognised specific positions of a phospho-ERK peptide sequence through its active site, and the contact of STEP F311 with phospho-ERK V205 and T207 were crucial interactions. Taken together, our results not only provide the information for interactions between ERK and STEP, but will also help in the development of specific strategies to target STEP-ERK recognition, which could serve as a potential therapy for neurological disorders. Regulation of phospho-ERK by STEP underlies important neuronal activities. A detailed enzymologic characterisation and cellular studies of STEP revealed that specific residues in KIM and active site mediated ERK recognition. Structural differences between the KIM-ERK interfaces and the active site among different ERK phosphatases could be targeted to develop specific STEP inhibitor, which has therapeutic potential for neurological disorders. PKA, protein kinase A & NGF, nerve growth factor.