LncRNA XIST regulates osteoclast formation and promotes orthodontically induced inflammatory root resorption through miR-130b-3p/PTEN axis.

The long non-coding RNA (LncRNA) X-inactive specific transcript (XIST) regulates the biological process of osteoclasts and the process of related diseases. This study was attempted to investigate the mechanism of LncRNA XIST acting in osteoclast formation and orthodontic induced inflammatory root resorption (OIIRR). The compression force (CF) -induced cell model and the orthodontic tooth movement (OTM) rat model were designed and established in this study. The expression of LncRNA XIST, miR-130b-3p, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) as well as osteoclast related marker genes and inflammatory factors level were measured in this study. The interaction among LncRNA XIST, microRNA-130b-3p (miR-130b-3p) and PTEN were researched through luciferase activity and western blot assay. Pathological sections were used to analyze root resorption and osteoclast formation. The OTM rat model was successfully constructed, which was characterized by increased tooth spacing and increased root resorption pits. PTEN and LncRNA XIST was overexpressed in OTM group. Mechanism analysis showed that the overexpression of LncRNA XIST enhanced the PTEN level by sponging miR-130b-3p. The overexpression of LncRNA XIST increased the secretion of inflammatory factors and positive osteoclasts number, but inhibited the differentiation of osteoclasts by sponging miR-130b-3p and promoting the level of PTEN. This finding demonstrates that LncRNA XIST regulates osteoclast formation and aggravated OIIRR through miR-130b-3p/PTEN axis, suggesting that LncRNA XIST may be used as potential targets for OIIRR therapy.

HDAC2 as a target for developing anti-cancer drugs.

Histone deacetylases (HDACs) deacetylate histones H3 and H4. An imbalance between histone acetylation and deacetylation can lead to various diseases. HDAC2 is present in the nucleus. It plays a critical role in modifying chromatin structures and regulates the expression of various genes by functioning as a transcriptional regulator. The roles of HDAC2 in tumorigenesis and anti-cancer drug resistance are discussed in this review. Several reports suggested that HDAC2 is a prognostic marker of various cancers. The roles of microRNAs (miRNAs) that directly regulate the expression of HDAC2 in tumorigenesis are also discussed in this review. This review also presents HDAC2 as a valuable target for developing anti-cancer drugs.

The identification of a PTEN-associated gene signature for the prediction of prognosis and planning of therapeutic strategy in endometrial cancer.

Background: Endometrial cancer (EC) is one of the most common malignancies among women. To improve the prognosis and treatment of EC, finding out a phosphatase and tensin homolog deleted on chromosome 10 (PTEN)-associated prognostic signature would be beneficial. Methods: EC clinical data, genetic mutation data, and transcriptome data were downloaded from The Cancer Genome Atlas (TCGA) database. To clarify the specific PTEN-associated signature, cox regression analyses were performed. The clinical value of the selected signature on the overall survival (OS) and the secretoglobin family 2A member 1 (SCGB2A1)-independent analysis, immune and functional analysis were investigated respectively. Results: Five hundred and fourteen EC samples were screened and PTEN mutation occupied 57%. Enrichment analysis indicated that mutant-type PTEN was enriched for pathways related to the upregulated human T-cell leukemia virus-1 (HTLV-1) infection and estrogen signaling pathway. SCGB2A1 was identified by cox regression analysis. Immune analysis exhibited significant immune infiltration with higher expression of T cells, B cells, and macrophage groups. Immune-checkpoint transcripts CD274 molecule (CD274), and cytotoxic T-lymphocyte associated protein 4 (CTLA4), hepatitis A virus cellular receptor 2 (HAVCR2), lymphocyte activation gene 3 (LAG3), programmed cell death 1 (PDCD1), PDCD1 ligand 2 (PDCD1LG2), T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT), and sialic acid binding immunoglobulin like lectin 15 (SIGLEC15) were discovered statistically different. In addition, the low-SCGB2A1 group had worse OS than the high-SCGB2A1 group. SCGB2A1 showed significant area under the curve (AUC) values in a time-dependent receiver operating characteristic (ROC) analysis. Prevalence of microsatellite instability (MSI) was detected and SCGB2A1 showed a negative correlation with EC. Immune checkpoint blockade (ICB) response indicated a worse immune response in the low-SCGB2A1 group. The distribution of one-class linear regression (OCLR) scores reflected the negative correlation between messenger RNA expression-based stemness index (mRNAsi) and prognostic gene expression. Furthermore, several SCGB2A1-related signaling pathways in EC were identified. Conclusions: SCGB2A1 is a prognostic immunometabolic signature for patients with EC, which may help improve the prognosis and therapeutic effect.

Suppression of hepatocellular carcinoma progression by long noncoding RNA apolipoprotein C1 pseudogene via the regulation of the microRNA-106b-PTEN axis.

Background: Numerous researches have reported that long noncoding RNAs (lncRNAs) participate in tumor development and progression. LncRNA apolipoprotein C-I pseudogene 1 (APOC1P1), a pseudogene located in 19q13.2 between apolipoprotein C-I and apolipoprotein C-IV, is involved in a variety of diseases. However, the role of lncRNA APOC1P1 in hepatocellular carcinoma (HCC) remains unknown. Methods: Quantitative polymerase chain reaction (qPCR) was performed to examine the expression of APOC1P1, miR-106b, and PTEN (phosphatase and TENsin homolog deleted on chromosome 10) in HCC tissues, adjacent normal tissues, and specific cell lines (LO2, Bel-7407, HCCLM3, MHCC-97H, Hep G2, and Huh-7). Upregulation of APOC1P1 and downregulation of miR-106b were conducted via application of vector transfection and microRNA (miRNA) inhibitor. Bioinformatics analysis and luciferase reporter assay were used to verify the binding sites of APOC1P1, miR-106b, and PTEN. Cell proliferation and invasion were determined with Cell Counting Kit-8 (CCK-8) and Transwell experiments. Subcellular location analysis was used to determine the distribution of APOC1P1 in cells, and Western blotting was used to detect the expression of PTEN. Results: It was found that the expressions of APOC1P1 and PTEN were downregulated, while that of miR-106b was upregulated in HCC tissues and cells. Subcellular location analysis showed that APOC1P1 was localized in cytoplasm and competitively bound to miR-106b. APOC1P1 overexpression and miR-106b inhibition suppressed HCC cell proliferation and invasion. qPCR indicated the negative correlation between APOC1P1 expression and miR-106b expression in HCC tissues and a positive correlation between APOC1P1 and PTEN. Conclusions: Our findings suggested that the lncRNA APOC1P1 inhibits HCC progression by competitively binding to miR-106b, leading to elevated PTEN expression, inhibiting cell proliferation and invasion in HCC cells. These results provide new insights into the diagnosis and therapy of HCC.

Implications of miR-148a-3p/p35/PTEN signaling in tau hyperphosphorylation and autoregulatory feedforward of Akt/CREB in Alzheimer's disease.

Existing studies have revealed that microRNAs (miRNAs) have a role in cognitive deficits in Alzheimer's disease (AD). However, the function and pathophysiological mechanism of deregulated miRNAs underlying AD pathology remain to be investigated. The present study aimed to clarify the role and mechanism of miR-148a-3p in AD. RNA sequencing, qRT-PCR, and western blot analysis were used to identify the aberrant expression and signaling of miR-148a-3p within cells, mice, and patients with AD. Molecular biology techniques involving luciferase reporter assays, gene overexpression and silencing, chromatin immunoprecipitation, and adeno-associated virus-based miRNA overexpression were used to explore the biological function and mechanisms of miR-148a-3p. Downregulation of miR-148a-3p was identified in AD. Upregulation of miR-148a-3p was found to protect neuronal cells against Aß-associated tau hyperphosphorylation by directly targeting p35/CDK5 and PTEN/p38 mitogen-activated protein kinase (MAPK) pathways. A mutual regulatory link between miR-148a-3p and PTEN using a feedforward arrangement was confirmed via promotion of transcription and expression of miR-148a-3p by way of the PTEN/Akt/CREB pathway. Significantly, in vivo targeting of miR-148a-3p signaling ameliorated cognitive deficits by decreasing p35/PTEN-elicited tau hyperphosphorylation, accompanied by feedforward transduction of the PTEN/Akt/CREB pathway. In conclusion, the present study implicated the miR-148a-3p/p35/PTEN pathway as an essential contributor to tau hyperphosphorylation and feedforward regulation in AD.

Identification of a Cowden syndrome patient with a novel PTEN mutation and establishment of patient-derived induced pluripotent stem cells.

Cowden syndrome (CS) is an autosomal dominant inherited disorder characterized by multiple hamartomas in various organs such as the mucosa, skin, and gastrointestinal tract. Patients with CS are at high risk for breast and thyroid cancers. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor gene that negatively regulates the AKT pathway, and PTEN mutations are known to be the major causes of this syndrome. However, the pathogenesis of this syndrome has not been clarified. Here, we present a case of a Japanese woman with multiple oral polyps, breast cancer, and thyroid cancer who was clinically diagnosed with CS. We obtained DNA and RNA samples from the patient's peripheral blood mononuclear cells (PBMCs) and buccal mucosa tumor. Next-generation sequencing revealed novel germline mutations (c.1020delT and c.1026G > A) in exon 8 of PTEN. Sanger sequencing identified no PTEN transcript from the mutant allele. Furthermore, CS-specific induced pluripotent stem cells (CS-iPSCs) were established from PBMCs of the patient under feeder- and serum-free culture. Compared with healthy PBMCs and iPSCs, both of the CS-derived PBMCs and CS-iPSCs exhibited significantly reduced expression of the PTEN transcript. The transcriptional variant, PTENδ, was increased in CS-iPSCs, suggesting that it may be the cause of the disease.

Mesenchymal Stem Cell-derived Extracellular Vesicles Transmitting MicroRNA-34a-5p Suppress Tumorigenesis of Colorectal Cancer Through c-MYC/DNMT3a/PTEN Axis.

Mesenchymal stem cell-derived extracellular vesicles (MSC-EV) can transport microRNAs (miRNAs) into colorectal cancer (CRC) cells, thus to inhibit the malignant phenotype of cancer cells. Whether MSC-EV could deliver miR-34a-5p to suppress CRC development was surveyed through the research. miR-34a-5p, c-MYC, DNA methyltransferase 3a (DNMT3a), and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression were measured in CRC tissues and cell lines. miR-34a-5p and c-MYC expression were altered by transfection in HCT-116 cells. MSC-EV were transfected with miR-34a-5p- and c-MYC-related oligonucleotides and co-cultured with HCT-116 cells. HCT-116 cell growth after treatment was observed. Furthermore, the functional roles of miR-34a-5p and c-MYC were explored in vivo. The combined interactions of miR-34a-5p/c-MYC/DNMT3a/PTEN axis were assessed. miR-34a-5p and PTEN were downregulated while c-MYC and DNMT3a were upregulated in CRC. Depletion of miR-34a-5p drove while that of c-MYC restricted CRC cell growth. MSC-EV retarded CRC progression. Moreover, MSC-EV carrying overexpressed miR-34a-5p or depleted c-MYC further disrupted CRC cell progression. miR-34a-5p targeted c-MYC to regulate DNMT3a and PTEN. c-MYC overexpression abrogated EV-derived miR-34a-5p upregulation-induced effects on CRC. Restoring miR-34a-5p or depleting c-MYC in MSC-EV limited CRC tumor formation. MSC-EV-derived miR-34a-5p depresses CRC development through modulating the binding of c-MYC to DNMT3a and epigenetically regulating PTEN.

Elevated Sodium Pump α3 Subunit Expression Promotes Colorectal Liver Metastasis via the p53-PTEN/IGFBP3-AKT-mTOR Axis.

The sodium pump α3 subunit is associated with colorectal liver metastasis. However, the underlying mechanism involved in this effect is not yet known. In this study, we found that the expression levels of the sodium pump α3 subunit were positively associated with metastasis in colorectal cancer (CRC). Knockdown of the α3 subunit or inhibition of the sodium pump could significantly inhibit the migration of colorectal cancer cells, whereas overexpression of the α3 subunit promoted colorectal cancer cell migration. Mechanistically, the α3 subunit decreased p53 expression, which subsequently downregulated PTEN/IGFBP3 and activated mTOR, leading to the promotion of colorectal cancer cell metastasis. Reciprocally, knockdown of the α3 subunit or inhibition of the sodium pump dramatically blocked this effect in vitro and in vivo via the downregulation of mTOR activity. Furthermore, a positive correlation between α3 subunit expression and mTOR activity was observed in an aggressive CRC subtype. Conclusions: Elevated expression of the sodium pump α3 subunit promotes CRC liver metastasis via the PTEN/IGFBP3-mediated mTOR pathway, suggesting that sodium pump α3 could represent a critical prognostic marker and/or therapeutic target for this disease.

miR-17-5p attenuates kidney ischemia-reperfusion injury by inhibiting the PTEN and BIM pathways.

BACKGROUND: Kidney ischemia-reperfusion (I/R) injury is an independent risk factor for delayed graft function after kidney transplantation with long-term graft survival deterioration. Previously, we found that the upregulated expression of miR-17-5p exerts a protective effect in kidney I/R injury, but the mechanism has not been clearly studied. METHODS: A kidney I/R injury model was induced in adult C57BL/6 male mice (20-22 g) by clamping both kidney pedicles for 30 min. The miR-17-5p agomir complex was injected into mice 24 h before surgery via the tail vein at a total injection volume of 10 µL/g body weight. The mice were euthanized on post-I/R injury day 2, and kidney function, apoptosis, autophagy, and related molecules were then detected. Human kidney-2 (HK-2) cells, which underwent hypoxia/reoxygenation, were treated with the miR-17-5p agomir, miR-17-5p antagomir, and small interfering ribonucleic acids (siRNAs). Cell viability, apoptosis, autophagy, and molecules were also examined. RESULTS: Autophagy, miR-17-5p expression, and kidney function damage were significantly more increased in the I/R group than in the sham group. In the cultured HK-2 cells underwent hypoxia/reoxygenation, the miR-17-5p agomir directly inhibited the expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and Bcl-2 like protein 11 (BIM), and attenuated apoptosis and autophagy. Further, miR-17-5p inhibited autophagy by activating the protein kinase B (Akt)/Beclin1 pathway, which was suppressed by siRNAs. Additionally, the administration of miR-17-5p agomir greatly improved kidney function in the I/R mice group by inhibiting autophagy and apoptosis. CONCLUSIONS: These findings suggest a new possible therapeutic strategy for the prevention and treatment of kidney I/R injury. The upregulation of miR-17-5p expression appears to inhibit apoptosis and autophagy by suppressing PTEN and BIM expression, which in turn upregulates downstream Akt/Beclin1 expression.

PTEN Hamartoma Tumor Syndrome: Skin Manifestations and Insights Into Their Molecular Pathogenesis.

Germline PTEN pathogenic variants cause a spectrum of disorders collectively labeled PTEN Hamartoma Tumor Syndrome (PHTS) and featured by hamartomas, developmental anomalies and increased cancer risk. Studies on experimental models provided evidence that PTEN is a "haploinsufficient" tumor-suppressor gene, however, mechanisms involved in the pathogenesis of clinical manifestations in PHTS patients remain elusive. Beyond analyzing clinical and molecular features of a series of 20 Italian PHTS patients, we performed molecular investigations to explore the mechanisms involved in the pathogenesis of PTEN-associated manifestations, with special focus on mucocutaneous manifestations. Typical mucocutaneous features were present in all patients assessed, confirming that these are the most important clue to the diagnosis. The most frequent were papules located in the trunk or extremities (73.7%), oral mucosa papules (68.4%), acral/palmoplantar keratosis and facial papules (both 57.9%), according with literature data. Molecular analyses on one trichilemmoma suggested that the wild-type PTEN allele was retained and expressed, reinforcing the evidence that PTEN does not require a second somatic hit to initiate pathogenic processes. Unexpectedly, one patient also displayed a cutaneous phenotype consistent with atypical mole/melanoma syndrome; no variants were detected in known melanoma genes, but Whole Exome Sequencing showed the rare truncating variant c.495G>A in the CDH13 gene that might have cooperated with PTEN-haploinsufficiency to generate such phenotype. Our findings confirm the reproducibility of known PHTS manifestations in real-world practice, highlighting the role of mucocutaneous manifestations in facilitating prompt diagnosis of the syndrome, and provide some insights into the pathogenic process induced by PTEN alterations, which may contribute to its understanding.

PTEN Expression Regulates Gap Junction Connectivity in the Retina.

Manipulation of the phosphatase and tensin homolog (PTEN) pathway has been suggested as a therapeutic approach to treat or prevent vision loss due to retinal disease. In this study, we investigated the effects of deleting one copy of Pten in a well-characterized class of retinal ganglion cells called α-ganglion cells in the mouse retina. In Pten +/- retinas, α-ganglion cells did not exhibit major changes in their dendritic structure, although most cells developed a few, unusual loop-forming dendrites. By contrast, α-ganglion cells exhibited a significant decrease in heterologous and homologous gap junction mediated cell coupling with other retinal ganglion and amacrine cells. Additionally, the majority of OFF α-ganglion cells (12/18 cells) formed novel coupling to displaced amacrine cells. The number of connexin36 puncta, the predominant connexin that mediates gap junction communication at electrical synapses, was decreased by at least 50% on OFF α-ganglion cells. Reduced and incorrect gap junction connectivity of α-ganglion cells will affect their functional properties and alter visual image processing in the retina. The anomalous connectivity of retinal ganglion cells would potentially limit future therapeutic approaches involving manipulation of the Pten pathway for treating ganglion cell degeneration in diseases like glaucoma, traumatic brain injury, Parkinson's, and Alzheimer's diseases.

[Role of PTEN in FAK and α-SMA protein levels changes in human embryonic lung fibroblasts induced by silica].

OBJECTIVE: To investigate the roles of phosphatase and tensin homolog deleted on chromosome 10(PTEN) in focal adhesion kinase(FAK) and α-smooth muscle actin(α-SMA) protein levels changes in human embryonic lung fibroblasts(HELFs) induced by silica. METHODS: The HELF cells were cultured in low serum medium containing 0, 25, 50, 100 and 200 µg/cm~2 silica for 24 hours, and the cell counting kit-8(CCK8) experiment was used to determine the appropriate dose of silica for stimulation. Meanwhile, the effect of different doses of silica on the morphology of HELFs was observed under inverted microscope. 50 µg/cm~2 silica solution was used to culture HELFs for 0, 1, 2, 4, 8, 12 and 24 hours(h), and the control group were used as the control group. In addition, Western blot was used to detect HELFs PTEN, p-PTEN, FAK, p-FAK and α-SMA protein levels at each culture time. Besides, HELFs were cultured with 2×10~(-3) mol/L PTEN inhibitor(VO-Ohpic) and/or silica for 24 h, including HELFs group, HELFs plus silica group, and HELFs plus silica plus VO-Ohpic group, and the FAK, p-FAK and α-SMA in each group were also detected by Western blot. RESULTS: With the increase of silica dose, HELFs viability firstly increased and then decreased, and the cell viability of 50 µg/cm~2 group(144. 91±5. 10) was significantly higher than that of 0 µg/cm~2 group(101. 23±6. 57)(P<0. 05). Compared with the control group of silica treated HELFs, the expression levels of PTEN and p-PTEN at 12 h and 24 h were significantly decreased(PTEN: 0. 44±0. 08 at 12 h, 0. 25±0. 02 at 24 h; p-PTEN: 0. 09±0. 01 at 12 h, 0. 01±0. 00 at 24 h; all P values<0. 05); whereas, FAK at 12 h(0. 92±0. 05) and 24 h(0. 89±0. 01), and p-FAK(0. 77±0. 02) and α-SMA at 24 h(1. 32±0. 01) were significantly increased(all P values<0. 05). The expression levels of FAK(0. 25±0. 03), p-FAK(0. 40±0. 02) and α-SMA(0. 36±0. 01) of HELFs plus silica plus VO-Ohpic group were significantly higher than those of HELFs plus silica group(P<0. 05). CONCLUSION: While silica induces HELFs FAK, p-FAK, and α-SMA increase, PTEN may downregulate FAK, p-FAK and α-SMA expression levels.

Glycogen Synthase Kinase-3 Beta Expression Correlates With Worse Overall Survival in Non-Small Cell Lung Cancer-A Clinicopathological Series.

BACKGROUND: Glycogen Synthase Kinase-3 beta (GSK-3ß) regulates diverse cell functions including metabolic activity, signaling and structural proteins. GSK-3ß phosphorylates target pro-oncogenes and regulates programmed cell death-ligand 1 (PD-L1). This study investigated the correlation between GSK-3ß expression and clinically relevant molecular features of lung adenocarcinoma (PDL1 score, PTEN expression and driver mutations). METHODS: We evaluated 95 lung cancer specimens from biopsies and surgical resections. Immunohistochemistry was performed to analyze the expression of GSK-3ß, PTEN, and PDL1. Epidemiological data, molecular characteristics and staging were evaluated from medical records. The histologic classification was performed by an experienced pulmonary pathologist. RESULTS: Most patients were female (52.6%) and the majority had a positive smoking history. The median age was 68.3 years, with individuals over 60 years accounting for 82.1%. The predominant histological subtype was adenocarcinoma (69.5%), followed by squamous cell carcinoma (20.0%). GSK-3ß expression in tumors was cytoplasmic with a dotted pattern and perinuclear concentration, with associated membranous staining. Seven (7.3%) tumors had associated nuclear expression localization. Seventy-seven patients (81.1%) had advanced clinical-stage tumors. GSK-3ß was positive in 75 tumors (78%) and GSK3-positive tumors tended to be diagnosed at advanced stages. Among stage III/IV tumors, 84% showed GSK3 positivity (p= 0.007). We identified a statistically significant association between GSK-3ß and PTEN in the qualitative analysis (p 0.021); and when comparing PTEN to GSK-3ß intensity 2+ (p 0.001) or 3+ expression (> 50%) - p 0.013. GSK-3ß positive tumors with a high histological score had a worse overall survival. CONCLUSION: We identified the histological patterns of GSK-3ß expression and evaluated its potential as marker for overall survival, establishing a simple histological score to measure the evaluated status in resected tissues. The use of GSK-3ß expression as an immune response biomarker remains a challenge. Future studies will seek to explain the role of its interaction with PTEN.

Downregulation of microRNA­25­3p inhibits the proliferation and promotes the apoptosis of multiple myeloma cells via targeting the PTEN/PI3K/AKT signaling pathway.

Numerous studies have confirmed that microRNAs (miRNAs or miRs) have important roles in cancer biogenesis and development including multiple myeloma (MM). MicroRNA­25­3p (miR­25­3p) has been proven to promote cancer progression, whereas its functions in MM has not yet been reported, at least to the best of our knowledge. Therefore, the present study aimed to investigate the function of miR­25­3p in MM and to identify the potential underlying mechanistic pathway. Herein, it was found that miR­25­3p expression was significantly increased in MM tissues and cell lines. The upregulation of miR­25­3p was closely associated with anemia, renal function impairment international staging system (ISS) staging and Durie­Salmon (D­S) staging. A high level of miR­25­3p was predictive of a poor prognosis of patients with MM. In vitro, the knockdown of miR­25­3p suppressed the proliferation and promoted the apoptosis of RPMI­8226 and U266 cells, while the overexpression of miR­25­3p exerted opposite effects. In addition, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a well­known tumor suppressor, was confirmed as a target of miR­25­3p in MM cells. Moreover, it was found that the PTEN expression levels were decreased, and inversely correlated with miR­25­3p expression levels in MM tissues. Further analyses revealed that the overexpression of PTEN exerted effects similar to those of miR­25­3p knockdown, whereas the knockdown of PTEN partially abolished the effects of miR­25­3p inhibitor on MM cells. Accompanied by PTEN induction, miR­25­3p promoted PI3K/AKT signaling pathway activation in MM cells. Collectively, these findings demonstrate critical roles for miR­25­3p in the pathogenesis of MM, and suggest that miR­25­3p may serve as a novel prognostic biomarker and therapeutic target of MM.

Corrigendum: PTEN: A Thrifty Gene That Causes Disease in Times of Plenty?

[This corrects the article DOI: 10.3389/fnut.2020.00081.].

Evaluation of PTEN Inhibitor Following Spinal Cord Injury on Recovery of Voiding Efficiency and Motor Function Observed by Regeneration in Spinal Cord.

PURPOSE: Neurogenic bladder (NB) associated with spinal cord injury (SCI) is a serious health problem. However, no effective treatment has been developed for SCI patients with NB. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibitors have been proposed as a promising option for inducing neural regeneration. Therefore, we investigated the effects of a tissue gene nerve (TGN), PTEN inhibitor, on voiding function, motor function, and the expression of growth factors after SCI. METHODS: In this experiment, female rats were randomly divided into 3 groups (n=10 in each group): the sham-operation group, the SCI-induced group, and the SCI-induced and TGN-treated group. Cystometry; the Basso, Beattie, and Bresnahan (BBB) scale test; the ladder walking test; hematoxylin and eosin staining; and Western blotting for brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and nerve growth factor (NGF) were performed to evaluate functional and molecular changes. RESULTS: After SCI, the rats exhibited decreased walking ability according to the BBB scale test and impaired coordinative function according to the ladder walking test. The PTEN inhibitor promoted enhanced walking ability and coordinative function. Cystometry showed voiding impairment after SCI and improved voiding function was observed after PTEN treatment. Overexpression of VEGF, BDNF, and NGF were observed after SCI. Administration of PTEN inhibitors significantly attenuated the overexpression of growth factors due to SCI. CONCLUSION: PTEN inhibitor treatment diminished the overexpression of growth factors and promoted the repair of damaged tissue. PTEN inhibitor-treated rats also showed improved motor function and improved voiding function. Therefore, we suggest TGN as a new therapeutic agent that can be applied after SCI.

Upregulation of C Terminus of Hsc70-Interacting Protein Attenuates Apoptosis and Procoagulant Activity and Facilitates Brain Repair After Traumatic Brain Injury.

Traumatic brain injury (TBI) could highly induce coagulopathy through breaking the dynamic balance between coagulation and fibrinolysis systems, which may be a major contributor to the progressive secondary injury cascade that occurs after TBI. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibition is reported to exert neuroprotection in TBI, making it a potential regulatory target involved in TBI-induced coagulation disorder. PTEN level is controlled in a major way by E3 ligase-mediated degradation through the ubiquitin-proteasome system. The C terminus of Hsc70-interacting protein (CHIP) has been shown to regulate proteasomal degradation and ubiquitination level of PTEN. In the present study, CHIP was overexpressed and knocked down in mouse brain microvascular endothelial cells (bEnd.3) and tissues during the early phase of TBI. In vitro cell proliferation, cell apoptosis, migration capacity, and invasion capacity were determined. The changes of procoagulant and apoptosis molecules after TBI were also detected as well as the micrangium density and blood-brain barrier permeability after in vivo TBI. In vitro results demonstrated that CHIP overexpression facilitated bEnd.3 cell proliferation, migration, and invasion and downregulated cell apoptosis and the expressions of procoagulant molecules through promoting PTEN ubiquitination in a simulated TBI model with stretch-induced injury treatment. In vivo experiments also demonstrated that CHIP overexpression suppressed post-TBI apoptosis and procoagulant protein expressions, as well as increased microvessel density, reduced hemorrhagic injury, and blood-brain barrier permeability. These findings suggested that the upregulation of CHIP may attenuate apoptosis and procoagulant activity, facilitate brain repair, and thus exerts neuroprotective effects in TBI.

HBV infection exacerbates PTEN defects in hepatocellular carcinoma through upregulation of miR-181a/382/362/19a.

A high hepatitis B virus (HBV) load and chronic hepatitis B infection are well-recognized risk factors for the development of hepatocellular carcinoma (HCC), highlighting the need for research into the mechanisms underlying the role of HBV infection in HCC. Because phosphatase and tensin homolog (PTEN) has been implicated in HCC development, we explored whether PTEN has a role in HBV-related hepatocarcinogenesis. We found that PTEN expression was correlated with advanced clinicopathological features and that HBV infection exacerbates PTEN defects in HCC. Using an integrated approach, we then investigated if miRNAs linked HBV infection to PTEN downregulation in HCC and found that PTEN was a target of miR-181a/382/362/19a. We also show that miR-181a/382/362/19a-mediated inhibition of PTEN led to an enhanced malignant phenotype and stimulation of AKT signaling in HCC cells. Collectively, our results indicate that HBV infection exacerbates PTEN defects in hepatocellular carcinoma through upregulation of miR-181a/362/382/19a. Our work implicates miR-181a/362/382/19a and PTEN as potential biomarkers and targets for novel prognostic, diagnostic, and therapeutic strategies targeting HBV-related HCC.