Split ring multiband refractive index cancer sensor based on terahertz radiation.

A design of a multiband terahertz (THz) metamaterial biosensor for early cancer detection is proposed. The THz biosensor composed of several arc-shaped connecting parts operates at three different frequencies, and the absorptivity of the three resonant frequencies exceeds 99% in free space. In this work, we analyzed the absorption spectrum and polarization independence under different design parameters, improved the performance of the sensor by adjusting the absorption characteristics of the sensor, and gave the calculation results. Additionally, we studied the influence of the refractive index and thickness of different samples on the sensor, and theoretically calculated the sensitivity of the sensor to basal cells, breast cells, cervical cells, and their corresponding cancer cells. The result shows that the maximum sensitivity of the sensor can reach 642.5 GHz/RIU, which is much higher than the reported biosensors. Therefore, the proposed THz sensor has great potential in early detection and early warning of cancer.

A Novel ASCT2 Inhibitor, C118P, Blocks Glutamine Transport and Exhibits Antitumour Efficacy in Breast Cancer.

BACKGROUND: The microtubule protein inhibitor C118P shows excellent anti-breast cancer effects. However, the potential targets and mechanisms of C118P in breast cancer remain unknown. METHODS: Real-time cellular analysis (RTCA) was used to detect cell viability. Apoptosis and the cell cycle were detected by flow cytometry. Computer docking simulations, surface plasmon resonance (SPR) technology, and microscale thermophoresis (MST) were conducted to study the interaction between C118P and alanine-serine-cysteine transporter 2 (ASCT2). Seahorse XF technology was used to measure the basal oxygen consumption rate (OCR). The effect of C118P in the adipose microenvironment was explored using a co-culture model of adipocytes and breast cancer cells and mouse cytokine chip. RESULTS: C118P inhibited proliferation, potentiated apoptosis, and induced G2/M cell cycle arrest in breast cancer cells. Notably, ASCT2 was validated as a C118P target through reverse docking, SPR, and MST. C118P suppressed glutamine metabolism and mediated autophagy via ASCT2. Similar results were obtained in the adipocyte-breast cancer microenvironment. Adipose-derived interleukin-6 (IL-6) promoted the proliferation of breast cancer cells by enhancing glutamine metabolism via ASCT2. C118P inhibited the upregulation of ASCT2 by inhibiting the effect of IL-6 in co-cultures. CONCLUSION: C118P exerts an antitumour effect against breast cancer via the glutamine transporter ASCT2.

RBM4 dictates ESCC cell fate switch from cellular senescence to glutamine-addiction survival through inhibiting LKB1-AMPK-axis.

Cellular senescence provides a protective barrier against tumorigenesis in precancerous or normal tissues upon distinct stressors. However, the detailed mechanisms by which tumor cells evade premature senescence to malignant progression remain largely elusive. Here we reported that RBM4 adversely impacted cellular senescence to favor glutamine-dependent survival of esophageal squamous cell carcinoma (ESCC) cells by dictating the activity of LKB1, a critical governor of cancer metabolism. The level of RBM4 was specifically elevated in ESCC compared to normal tissues, and RBM4 overexpression promoted the malignant phenotype. RBM4 contributed to overcome H-RAS- or doxorubicin-induced senescence, while its depletion caused P27-dependent senescence and proliferation arrest by activating LKB1-AMPK-mTOR cascade. Mechanistically, RBM4 competitively bound LKB1 to disrupt the LKB1/STRAD/MO25 heterotrimeric complex, subsequently recruiting the E3 ligase TRIM26 to LKB1, promoting LKB1 ubiquitination and degradation in nucleus. Therefore, such molecular process leads to bypassing senescence and sustaining cell proliferation through the activation of glutamine metabolism. Clinically, the ESCC patients with high RBM4 and low LKB1 have significantly worse overall survival than those with low RBM4 and high LKB1. The RBM4 high/LKB1 low expression confers increased sensitivity of ESCC cells to glutaminase inhibitor CB-839, providing a novel insight into mechanisms underlying the glutamine-dependency to improve the efficacy of glutamine inhibitors in ESCC therapeutics.

Recent advances in nanotechnology approaches for non-viral gene therapy.

Gene therapy has shown great potential in the treatment of many diseases by downregulating the expression of certain genes. The development of gene vectors as a vehicle for gene therapy has greatly facilitated the widespread clinical application of nucleic acid materials (DNA, mRNA, siRNA, and miRNA). Currently, both viral and non-viral vectors are used as delivery systems of nucleic acid materials for gene therapy. However, viral vector-based gene therapy has several limitations, including immunogenicity and carcinogenesis caused by the exogenous viral vectors. To address these issues, non-viral nanocarrier-based gene therapy has been explored for superior performance with enhanced gene stability, high treatment efficiency, improved tumor-targeting, and better biocompatibility. In this review, we discuss various non-viral vector-mediated gene therapy approaches using multifunctional biodegradable or non-biodegradable nanocarriers, including polymer-based nanoparticles, lipid-based nanoparticles, carbon nanotubes, gold nanoparticles (AuNPs), quantum dots (QDs), silica nanoparticles, metal-based nanoparticles and two-dimensional nanocarriers. Various strategies to construct non-viral nanocarriers based on their delivery efficiency of targeted genes will be introduced. Subsequently, we discuss the cellular uptake pathways of non-viral nanocarriers. In addition, multifunctional gene therapy based on non-viral nanocarriers is summarized, in which the gene therapy can be combined with other treatments, such as photothermal therapy (PTT), photodynamic therapy (PDT), immunotherapy and chemotherapy. We also provide a comprehensive discussion of the biological toxicity and safety of non-viral vector-based gene therapy. Finally, the present limitations and challenges of non-viral nanocarriers for gene therapy in future clinical research are discussed, to promote wider clinical applications of non-viral vector-based gene therapy.

Enhanced PDGFR/Wnt/ß-catenin activity of mesenchymal stem cells with high migration ability rescue bone loss of osteoporosis.

Osteoporosis is a widespread disease characterized by bone mass loss and microarchitectural deterioration. The side effects of clinical drugs make mesenchymal stem cells (MSCs)-based therapy gain increasing focus in the treatment of osteoporosis. MSCs need to migrate to the site of damage and undergo differentiation in order to participate in the subsequent bone repair process. Therefore, the homing ability of MSCs may be related to the repair ability. Here, we proposed a novel method to screen MSCs with high migration capacity and confirmed that these MSCs exhibited higher osteogenic differentiation ability both in vivo and in vitro. Further results indicated that MSCs with high migration ability could partly rescue the bone loss of ovarectomized (OVX) rats. Higher expression of Platelet-derived growth factors receptor ß- (PDGFRß) and more nuclear transduction of ß-catenin in MSCs with high migration ability may be responsible for biological functions. This article may provide a method to improve the efficacy of MSCs-based therapy in the clinic.

Choroid plexus-selective inactivation of adenosine A2A receptors protects against T cell infiltration and experimental autoimmune encephalomyelitis.

BACKGROUND: Multiple sclerosis (MS) is one of the most common autoimmune disorders characterized by the infiltration of immune cells into the brain and demyelination. The unwanted immunosuppressive side effect of therapeutically successful natalizumab led us to focus on the choroid plexus (CP), a key site for the first wave of immune cell infiltration in experimental autoimmune encephalomyelitis (EAE), for the control of immune cells trafficking. Adenosine A2A receptor (A2AR) is emerging as a potential pharmacological target to control EAE pathogenesis. However, the cellular basis for the A2AR-mediated protection remains undetermined. METHODS: In the EAE model, we assessed A2AR expression and leukocyte trafficking determinants in the CP by immunohistochemistry and qPCR analyses. We determined the effect of the A2AR antagonist KW6002 treatment at days 8-12 or 8-14 post-immunization on T cell infiltration across the CP and EAE pathology. We determined the critical role of the CP-A2AR on T cell infiltration and EAE pathology by focal knock-down of CP-A2AR via intracerebroventricular injection of CRE-TAT recombinase into the A2ARflox/flox mice. In the cultured CP epithelium, we also evaluated the effect of overexpression of A2ARs or the A2AR agonist CGS21680 treatment on the CP permeability and lymphocytes migration. RESULTS: We found the specific upregulation of A2AR in the CP associated with enhanced CP gateway activity peaked at day 12 post-immunization in EAE mice. Furthermore, the KW6002 treatment at days 8-12 or 8-14 post-immunization reduced T cell trafficking across the CP and attenuated EAE pathology. Importantly, focal CP-A2AR knock-down attenuated the pathogenic infiltration of Th17+ cells across the CP via inhibiting the CCR6-CCL20 axis through NFκB/STAT3 pathway and protected against EAE pathology. Lastly, activation of A2AR in the cultured epithelium by A2AR overexpression or CGS21680 treatment increased the permeability of the CP epithelium and facilitated lymphocytes migration. CONCLUSION: These findings define the CP niche as one of the primary sites of A2AR action, whereby A2AR antagonists confer protection against EAE pathology. Thus, pharmacological targeting of the CP-A2AR represents a novel therapeutic strategy for MS by controlling immune cell trafficking across CP.

The interplay between mitochondria and store-operated Ca2+ entry: Emerging insights into cardiac diseases.

Store-operated Ca2+ entry (SOCE) machinery, including Orai channels, TRPCs, and STIM1, is key to cellular calcium homeostasis. The following characteristics of mitochondria are involved in the physiological and pathological regulation of cells: mitochondria mediate calcium uptake through calcium uniporters; mitochondria are regulated by mitochondrial dynamic related proteins (OPA1, MFN1/2, and DRP1) and form mitochondrial networks through continuous fission and fusion; mitochondria supply NADH to the electron transport chain through the Krebs cycle to produce ATP; under stress, mitochondria will produce excessive reactive oxygen species to regulate mitochondria-endoplasmic reticulum interactions and the related signalling pathways. Both SOCE and mitochondria play critical roles in mediating cardiac hypertrophy, diabetic cardiomyopathy, and cardiac ischaemia-reperfusion injury. All the mitochondrial characteristics mentioned above are determinants of SOCE activity, and vice versa. Ca2+ signalling dictates the reciprocal regulation between mitochondria and SOCE under the specific pathological conditions of cardiomyocytes. The coupling of mitochondria and SOCE is essential for various pathophysiological processes in the heart. Herein, we review the research focussing on the reciprocal regulation between mitochondria and SOCE and provide potential interplay patterns in cardiac diseases.

EGFR/EGFRvIII partly regulates the tumourigenesis of glioblastoma through the SOX9-GLUT3 axis.

EGFR/EGFR variant III (EGFRvIII) glioblastoma is seriously malignant, and the underlying mechanism remains unclear. In this study, EGFR and GLUT3 were found to be co-expressed in our collected tissues and associated with worse overall survival in glioblastoma via bioinformatics analysis. Functionally, in vitro and in vivo tests revealed that silencing GLUT3 substantially inhibited the viability of U87-EGFRvIII and LN229-EGFRvIII cells. Compared with wild-type U87 or LN229 cells, the expression level of SOX9 in U87-EGFRvIII or LN229-EGFRvIII cells (U87 and LN229 over-expressing EGFRvIII) was substantially increased. Chromatin immunoprecipitation and Dual-luciferase reporter assays revealed that SOX9 bound to the promoter of GLUT3 and promoted the expression of GLUT3. Collectively, our findings indicated that the EGFR/EGFRvIII-SOX9-GLUT3 axis mediated the tumourigenesis of glioblastoma and might be a potential target for glioblastoma therapy.

Diagnosis and treatment of obturator hernia: retrospective analysis of 86 clinical cases at a single institution.

BACKGROUND: To explore the clinical characteristics, diagnosis and treatment of obturator hernia. METHODS: Eighty-six patients who were diagnosed as obturator hernia by abdominal CT in the Department of Gastrointestinal Surgery of our hospital between 2009 and 2019 were enrolled in this study. Patient characteristics, surgical method, postoperative complications and mortalities were retrospectively reviewed. RESULTS: Thirty days mortality rate of 5.5% and 46.1% were observed in surgery group and non-surgery group, respectively. Surgery was performed as an emergency procedure in 59 cases and elective procedure in 14 cases depending on different hernia contents, intestinal necrosis and signs of peritonitis. In the emergency surgery group, segmental intestinal resection with anastomosis was performed in 24 patients (24/59, 40.7%). There were 4 deaths (4/59, 6.8%) in this group, all of which occurred in patients undergoing SI resections. In contrast, no bowel resection, postoperative complications, or death occurred in the elective surgery group. 3-year recurrence rates of 5.1% (3/59) and 7.1% (1/14) were observed in the emergency surgery and the elective surgery group, respectively. CONCLUSIONS: CT examination plays an important role in improving the diagnostic rate of obturator hernia. Timely surgical treatment is the key to improve the efficacy of obturator hernia and prevent the deterioration of the condition. In addition, intestinal resection and postoperative complications may be the important factors leading to postoperative death.

Association between Serum Uric Acid and Nonalcoholic Fatty Liver Disease in Nonobese Postmenopausal Women: A Cross-sectional Study.

This study aimed to determine the association between serum uric acid (sUA) and nonalcoholic fatty liver disease (NAFLD) in nonobese postmenopausal women. A total of 4323 female individuals over 18 years of age participated in this cross-sectional study. The subjects were divided into four groups according to menopause status and body mass index. sUA quartiles in this female population were categorized as follows: Q1 ≤ 230 mmol/L, Q2: 231-270 mmol/L, Q3: 271-310 mmol/L and Q4: ≥ 311 mmol/L. The presence or absence of NAFLD was assessed by abdominal ultrasonography. The prevalence of NAFLD was 38.8% in the general population, and the average age was 46.5 ± 11.3 years. Among nonobese and obese subjects, the prevalence of NAFLD was lower in nonmenopausal subjects than in postmenopausal subjects (nonobese: 20.74% vs 45.26%, respectively, P < 0.0001; obese: 70.51% vs 84.35%, respectively, P < 0.0001). After adjusting for age, current smoking status, current alcohol drinking status, diabetes, hypertension disease and triglyceride, the ORs (95% CIs) for NAFLD among individuals in Q2-Q4 were 1.518 (1.062-2.169), 1.431 (1.010-2.027) and 2.054 (1.442-2.927), respectively, P value for trend <0.0001. Higher sUA levels can be used as a predictive biomarker for NAFLD in nonobese postmenopausal women.

Is tubal endometriosis an asymmetric disease? A 17-year retrospective study.

PURPOSE: To investigate whether there are left-right asymmetries in tubal endometriosis and the factors affecting this predisposition. METHODS: Women who underwent salpingectomy for gynecological diseases and were diagnosed with tubal endometriosis between January 2002 and July 2019 were included in the study. The frequencies of left and right tubal endometriosis were compared with the expected 50% using a binominal test. The demographic characteristics and presence of ovarian endometrioid cysts, adenomyosis, and hydrosalpinx were also analyzed. RESULTS: During the study period of more than 17 years, 305 women were diagnosed with tubal endometriosis. The distribution of tubal endometriosis in the left or right fallopian tubes was analyzed. Tubal endometriosis was found in the left fallopian tube in 168 (55.08%) women, in the right fallopian tube in 93 (30.49%), and bilaterally in 44 (14.43%). Left unilateral tubal endometriosis was found most frequently (64.37%, 168/261), and its incidence was significantly higher than 50% (P < 0.001, binominal test). Furthermore, the frequency of left ovarian endometrioid cysts (58.82%) was higher than that of right ovarian endometrioid cysts (41.18%) (P < 0.001, binominal test). CONCLUSION: Our study confirms that tubal endometriosis is a left-side asymmetric disease, and this predisposition is highly consistent with ovarian endometrioid cysts, which supports the transplantation theory of the origin of endometriosis.

Canagliflozin impairs blood reperfusion of ischaemic lower limb partially by inhibiting the retention and paracrine function of bone marrow derived mesenchymal stem cells.

BACKGROUND: Canagliflozin (CANA) administration increases the risk of lower limb amputation in the clinic. The present study aimed to investigate whether and how CANA interferes with the intracellular physiological processes of bone marrow derived mesenchymal stem cells (BM-MSCs) and its contribution to ischaemic lower limb. METHODS: The in vivo blood flow recovery in ischaemic lower limbs following CANA treatment was evaluated. The cellular function of BM-MSCs after CANA treatment were also assessed in vitro. In silico docking analysis and mutant substitution assay were conducted to confirm the interaction of CANA with glutamate dehydrogenase 1 (GDH1). FINDINGS: Following CANA treatment, attenuated angiogenesis and hampered blood flow recovery in the ischaemic region were detected in diabetic and non-diabetic mice, and inhibition of the proliferation and migration of BM-MSCs were also observed. CANA was involved in mitochondrial respiratory malfunction in BM-MSCs and the inhibition of ATP production, cytochrome c release and vessel endothelial growth factor A (VEGFA) secretion, which may contribute to reductions in the tissue repair capacity of BM-MSCs. The detrimental effects of CANA on MSCs result from the inhibition of GDH1 by CANA (evidenced by in silico docking analysis and H199A-GDH1/N392A-GDH1 mutant substitution). INTERPRETATION: Our work highlights that the inhibition of GDH1 activity by CANA interferes with the metabolic activity of the mitochondria, and this interference deteriorates the retention of and VEGFA secretion by MSCs. FUNDING: National Natural Science Foundation of China, Natural Science Foundation of Zhejiang Province and Wenzhou Science and Technology Bureau Foundation.

Long noncoding RNA PCAT1, a novel serum-based biomarker, enhances cell growth by sponging miR-326 in oesophageal squamous cell carcinoma.

Long noncoding RNAs (lncRNAs) play important roles in the development and progression of human cancers. The lncRNA prostate cancer-associated transcript 1 (PCAT1) has been reported to be involved in multiple human cancers, including oesophageal squamous cell carcinoma (ESCC). However, the detailed biological functions, underlying mechanisms and clinical relevance of PCAT1 in ESCC remain unclear. Here, we confirmed that PCAT1 was highly expressed in ESCC tissues and cell lines. Knockdown of PCAT1 inhibited the growth of ESCC cells, whereas overexpression of PCAT1 showed the opposite effect both in vitro and in vivo. Moreover, knockdown of PCAT1 arrested the cell cycle at G2/M phase, reduced the expression of cyclin B1 and CDC2, and caused cells to be more sensitive to paclitaxel. Furthermore, PCAT1 could bind to miR-326, a tumour suppressor in diverse human cancers. Rescue experiments revealed that enforced expression of miR-326 attenuated the promotive effect of PCAT1 on ESCC cell growth. In addition, we discovered that PCAT1 was present in ESCC cell-derived exosomes, was higher in the serum of ESCC patients than those of healthy volunteer donors, and promoted cell growth through exosomes. Thus, our data indicate that PCAT1 promotes ESCC cell proliferation by sponging miR-326 and may serve as a non-invasive biomarker for ESCC.

Simultaneous Pulmonary Embolism and Ischemic Stroke in a Patient with Cor Biloculare after Glenn Anastomosis.

BACKGROUND: Cor biloculare, two-chambered heart due to the absence of atrial and ventricular septa, is a rare congenital heart anomaly. For Cor biloculare and other cardiac defects with single ventricle physiology, Glenn anastomosis has been developed as a palliative procedure. Thrombosis secondary to Glenn anastomosis in the patient with Cor biloculare could pose a serious threat to the survival, and has never been reported before. CASE REPORT: We report the case of a 27-year-old patient, with past history of Glenn anastomosis that was performed 7 years ago for the palliation of Cor biloculare. She presented with pulmonary embolism and ischemic stroke simultaneously at 7 days after Cesarean section. Due to her critical status, systemic anticoagulation with low-molecular-weight heparin was started immediately, followed by lifelong warfarin therapy. Pulmonary embolism regressed and neurological symptoms were considerably diminished after the anticoagulation treatment. CONCLUSION: This case illuminates the potential risk of thrombotic events in this patient cohort and demonstrates that anticoagulation therapy is an effective, secure, and appropriate for the management of this disease.

Topotecan induces apoptosis via ASCT2 mediated oxidative stress in gastric cancer.

BACKGROUND: Topotecan (TPT) is a Topo I inhibitor and shows obvious anti-cancer effects on gastric cancer. Cancer cells reprogram their metabolic pathways to increase nutrients uptake, which has already been a hallmark of cancer. But the effect of TPT on metabolism in gastric cancer remains unknown. PURPOSE: To investigate the effect of TPT on metabolism in gastric cancer. METHODS: ATP production was measured by ATP Assay kit. Glucose and glutamine uptake were measured by Glucose (HK) Assay Kit and Glutamine/Glutamate Determination Kit respectively. To detect glutathione (GSH) concentration and reactive oxygen species (ROS) generation, GSH and GSSG Assay Kit and ROS Assay Kit were adopted. Apoptosis rates, mitochondrial membrane potential (MMP) were determined by flow cytometry and protein levels were analyzed by immumohistochemical staining and western blotting. RESULTS: TPT increased ATP production. TPT promoted glucose uptake possibly via up-regulation of hexokinase 2 (HK2) or glucose transporter 1 (GLUT1) expression, while decreased glutamine uptake by down-regulation of ASCT2 expression. ASCT2 inhibitor GPNA and ASCT2 knockdown significantly suppressed the growth of gastric cancer cells. Inhibition of ASCT2 reduced glutamine uptake which led to decreased production of GSH and increased ROS level. ASCT2 knockdown induced apoptosis via the mitochondrial pathway and weakened anti-cancer effect of TPT. CONCLUSION: TPT inhibits glutamine uptake via down-regulation of ASCT2 which causes oxidative stress and induces apoptosis through the mitochondrial pathway. Moreover, TPT inhibits proliferation partially via ASCT2. These observations reveal a previously undescribed mechanism of ASCT2 regulated gastric cancer proliferation and demonstrate ASCT2 is a potential anti-cancer target of TPT.

A Novel Camptothecin Derivative 3j Inhibits Nsclc Proliferation Via Induction of Cell Cycle Arrest By Topo I-Mediated DNA Damage.

OBJECTIVE: The aim of this study is to investigate the inhibitory effect of camptothecin derivative 3j on Non-Small Cell Lung Cancer (NSCLCs) cells and the potential anti-tumor mechanisms. BACKGROUND: Camptothecin compounds are considered as the third largest natural drugs which are widely investigated in the world and they suffered restriction because of serious toxicity, such as hemorrhagic cystitis and bone marrow suppression. METHODS: Using cell proliferation assay and S180 tumor mice model, a series of 20(S)-O-substituted benzoyl 7- ethylcamptothecin compounds were screened and evaluated the antitumor activities in vitro and in vivo. Camptothecin derivative 3j was selected for further study using flow cytometry in NSCLCs cells. Cell cycle related protein cyclin A2, CDK2, cyclin D and cyclin E were detected by Western Blot. Then, computer molecular docking was used to confirm the interaction between 3j and Topo I. Also, DNA relaxation assay and alkaline comet assay were used to investigate the mechanism of 3j on DNA damage. RESULTS: Our results demonstrated that camptothecin derivative 3j showed a greater antitumor effect in eleven 20(S)-O-substituted benzoyl 7-ethylcamptothecin compounds in vitro and in vivo. The IC50 of 3j was 1.54± 0.41 µM lower than irinotecan with an IC50 of 13.86±0.80 µM in NCI-H460 cell, which was reduced by 8 fold. In NCI-H1975 cell, the IC50 of 3j was 1.87±0.23 µM lower than irinotecan (IC50±SD, 5.35±0.38 µM), dropped by 1.8 fold. Flow cytometry analysis revealed that 3j induced significant accumulation in a dose-dependent manner. After 24h of 3j (10 µM) treatment, the percentage of NCI-H460 cell in S-phase significantly increased (to 93.54 ± 4.4%) compared with control cells (31.67 ± 3.4%). Similarly, the percentage of NCI-H1975 cell in Sphase significantly increased (to 83.99 ± 2.4%) compared with control cells (34.45 ± 3.9%) after treatment with 10µM of 3j. Moreover, increased levels of cyclin A2, CDK2, and decreased levels of cyclin D, cyclin E further confirmed that cell cycle arrest was induced by 3j. Furthermore, molecular docking studies suggested that 3j interacted with Topo I-DNA and DNA-relaxation assay simultaneously confirmed that 3j suppressed the activity of Topo I. Research on the mechanism showed that 3j exhibited anti-tumour activity via activating the DNA damage response pathway and suppressing the repair pathway in NSCLC cells. CONCLUSION: Novel camptothecin derivative 3j has been demonstrated as a promising antitumor agent and remains to be assessed in further studies.

Adipocyte-derived IL-6 and leptin promote breast Cancer metastasis via upregulation of Lysyl Hydroxylase-2 expression.

BACKGROUND: Adipocytes make up the major component of breast tissue, accounting for 90% of stromal tissue. Thus, the crosstalk between adipocytes and breast cancer cells may play a critical role in cancer progression. Adipocyte-breast cancer interactions have been considered important for the promotion of breast cancer metastasis. However, the specific mechanisms underlying these interactions are unclear. In this study, we investigated the mechanisms of adipocyte-mediated breast cancer metastasis. METHODS: Breast cancer cells were cocultured with mature adipocytes for migration and 3D matrix invasion assays. Next, lentivirus-mediated loss-of-function experiments were used to explore the function of lysyl hydroxylase (PLOD2) in breast cancer migration and adipocyte-dependent migration of breast cancer cells. The role of PLOD2 in breast cancer metastasis was further confirmed using orthotopic mammary fat pad xenografts in vivo. Clinical samples were used to confirm that PLOD2 expression is increased in tumor tissue and is associated with poor prognosis of breast cancer patients. Cells were treated with cytokines and pharmacological inhibitors in order to verify which adipokines were responsible for activation of PLOD2 expression and which signaling pathways were activated in vitro. RESULTS: Gene expression profiling and Western blotting analyses revealed that PLOD2 was upregulated in breast cancer cells following coculture with adipocytes; this process was accompanied by enhanced breast cancer cell migration and invasion. Loss-of-function studies indicated that PLOD2 knockdown suppressed cell migration and disrupted the formation of actin stress fibers in breast cancer cells and abrogated the migration induced by following coculture with adipocytes. Moreover, experiments performed in orthotopic mammary fat pad xenografts showed that PLOD2 knockdown could reduce metastasis to the lung and liver. Further, high PLOD2 expression correlated with poor prognosis of breast cancer patients. Mechanistically, adipocyte-derived interleukin-6 (IL-6) and leptin may facilitate PLOD2 upregulation in breast cancer cells and promote breast cancer metastasis in tail vein metastasis assays. Further investigation revealed that adipocyte-derived IL-6 and leptin promoted PLOD2 expression through activation of the JAK/STAT3 and PI3K/AKT signaling pathways. CONCLUSIONS: Our study reveals that adipocyte-derived IL-6 and leptin promote PLOD2 expression by activating the JAK/STAT3 and PI3K/AKT signaling pathways, thus promoting breast cancer metastasis.

The role of ASCT2 in cancer: A review.

Reorganization of cellular metabolism is one of the hallmarks of cancer and many tumors show high glucose uptake and glutamine addiction. Glutamine is imported by the SLC family transporters from the microenvironment, and ASCT2 (encoded by the SLC1A5 gene) is recognized as a primary transporter. Of note, ASCT2 is overexpressed in different cancers and is closely related to poor prognosis. Nonetheless, the mechanisms regulating ASCT2 activity has not been elucidated. Moreover, several inhibitors of ASCT2 have emerged and shown a surprising antitumor effect. In conclusion, this review describes the function, regulatory mechanism, and inhibitors of ASCT2 in cancer, suggesting that high expression of ASCT2 is a promising prognostic marker and a potential drug target.

Osthole inhibits the PI3K/AKT signaling pathway via activation of PTEN and induces cell cycle arrest and apoptosis in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most common lethal tumors and is known to be lack of effective therapy. Thus, novel therapeutic strategies are greatly needed for treatment of ESCC. Osthole, a natural active extract, has been documented to have anti-tumor activity. However, the effect of osthole on ESCC cells has not been elucidated. In this study, we demonstrated that osthole could inhibit the ESCC cell proliferation in dose- and time-dependent manner. Osthole treatment also induced G2/M phase arrest and apoptosis of ESCC cells. Furthermore, upon exposure to osthole, the expression of Cyclin B1, Cdc2, Bcl-2, PARP1 and Survivin was decreased, while the expression of BAX, cleaved PARP1, cleaved Caspase3 and cleaved Caspase9 was increased. In addition, osthole treatment elicited upregulation of PTEN and downregulation of PI3K and phosphorylated AKT (p-AKT). Taken together, our study demonstrates that osthole could suppress ESCC proliferation through inducing cell cycle arrest and apoptosis. Moreover, PTEN-PI3K/AKT signaling pathway can be regulated by osthole. Our results indicate that osthole may find therapeutic application in the treatment of ESCC patients.

LncRNA SNHG16 Functions as an Oncogene by Sponging MiR-4518 and Up-Regulating PRMT5 Expression in Glioma.

BACKGROUND/AIMS: Long noncoding RNAs (lncRNAs) have recently emerged as novel and potentially promising therapeutic targets in various cancers. However, the expression pattern and biological function of lncRNAs in glioma remain largely elusive. In the present study, we investigated the functional role of an lncRNA, small nucleolar RNA host gene 16 (SNHG16), in glioma. METHODS: The expression levels of SNHG16 and miR-4518 were measured using qRT-PCR. The relationship between the levels of SNHG16 and clinicopathologic features were statically analyzed. The levels of proteins were detected using western blot. Bioinformatics analysis and luciferase reporter assays were applied to the analysis of the relationship between SNHG16, miR-4518 and PRMT5. Cell viability and apoptosis were measured using MTT and apoptosis ELISA assay, respectively. RESULTS: SNHG16 was highly expressed in glioma tissues and cell lines, which was related to poorer clinicopathologic features and shorter survival time. Knockdown of SNHG16 inhibits the viability and induces apoptosis of glioma cells. Further investigation revealed that SNHG16 could up-regulate the expression of miR-4518 targeted gene PRMT5 via acting as an endogenous sponge of miR-4518. Moreover, SNHG16 also affects the expression of Bcl-2 family proteins and the activation of PI3K/Akt signaling pathway. CONCLUSION: Our study revealed a novel SNHG16-miR-4518-PRMT5 pathway regulatory axis in glioma pathogenesis. SNHG16 could be used as a potential therapeutic target in the treatment of glioma.