PTEN Gene Research Articles

Fermentation Extract of Naringenin Increases the Expression of Estrogenic Receptor β and Modulates Genes Related to the p53 Signalling Pathway, miR-200c and miR-141 in Human Colon Cancer Cells Exposed to BPA.

The estrogenic receptor beta (ERβ) protects against carcinogenesis by stimulating apoptosis. Bisphenol A (BPA) is related to promoting cancer, and naringenin has chemoprotective activities both can bind to ERβ. Naringenin in the colon is metabolized by the microbiota. Cancer involves genetic and epigenetic mechanisms, including miRNAs. The objective of the present study was to evaluate the co-exposure effect of colonic in vitro fermented extract of naringenin (FEN) and BPA, to elucidate molecular effects in HT-29 colon cancer cell line. For this, we quantified genes related to the p53 signaling pathway as well as ERβ, miR-200c, and miR-141. As an important result, naringenin (IC50 250 µM) and FEN (IC50 37%) promoted intrinsic pathways of apoptosis through phosphatase and tensin homolog (PTEN) (+2.70, +1.72-fold, respectively) and CASP9 (+3.99, +2.03-fold, respectively) expression. BPA decreased the expression of PTEN (−3.46-fold) gene regulated by miR-200. We suggest that once co-exposed, cells undergo a greater stress forcing them to mediate other extrinsic apoptosis mechanisms associated with death domain FASL. In turn, these findings are related to the increase of ERβ (5.3-fold with naringenin and 13.67-fold with FEN) gene expression, important in the inhibition of carcinogenic development.

Cowden Disease: A Review.

PTEN hamartoma tumor syndrome (PTHS) includes diseases with germline pathogenic variants in the PTEN gene. Cowden syndrome is included in this syndrome . PTEN (phosphatase and tensin homolog) is a tumor suppressor gene located on chromosome 10q22-23; nearly 60%-90% of pathogenic variants are inherited. Cowden syndrome is a rare autosomic dominant condition, affecting approximately 1/200,000 people worldwide. Patients present benign and, malignant neoplasms in multiple organs, mostly breast and thyroid. The skin is the organ affected most consistently by Cowden disease. It is an autosomal dominant condition, characterized clinically by the presence of innumerable verrucous lesions on the skin. Interpretations of histopathologic findings in the cutaneous and mucosal lesions continue to be a matter of debate.

DNA Methyltransferase Inhibitor 5-AZA-DC Regulates TGFβ1-Mediated Alteration of Neuroglial Cell Functions after Oxidative Stress.

5-AZA-DC is an efficient methylation inhibitor that inhibits methylation of target DNA. In this study, we explored the effects of 5-AZA-DC on the regulation of TGFβ1 on target genes in neuroglial cell, as well as neuroglial cell functions under oxidative stress. The oxidative stress was constructed by editing CRISPR/Cas9 for knock out Ang-1 and ApoE4 genes. Cells were subjected to TGFβ1OE (or shTGFβ1) transfection and/or 5-AZA-DC intervention. Results showed that under oxidative stress, both TGFβ1OE and shTGFβ1 transfection raised DNMT1, but reduced TGFβ1, PTEN, and TSC2 expressions in neuroglial cells. TGFβ1 directly bind to the promoter of PTEN gene. 5-AZA-DC intervention lowered DNMT1 and raised TGFβ1 expression, as well as promoted the binding between TGFβ1 and promoter of PTEN. TGFβ1OE caused a significant increase in the DNA demethylation level of PTEN promoter, while 5-AZA-DC intervention reduced the DNA demethylation level of PTEN promoter. Under oxidative stress, TGFβ1OE (or shTGFβ1) transfection inhibited neuroglial cell proliferation, migration, and invasion, promoted cell apoptosis. 5-AZA-DC intervention alleviated TGFβ1OE (or shTGFβ1) transfection caused neuroglial cell proliferation, migration, and invasion inhibition, as well as cell apoptosis. To conclude, these results suggest that 5-AZA-DC can be used as a potential drug for epigenetic therapy on oxidative stress damage in neuroglial cells. The findings of this research provide theoretical basis and research ideas for methylation drug intervention and TGFβ1 gene as a possible precise target of glial oxidative stress diagnosis and treatment.

The Potential Application of Branch-PCR Assembled PTEN Gene Nanovector in Lung Cancer Gene Therapy.

Gene therapy offers an alternative and promising avenue to lung cancer treatment. Here, we used dibenzocyclooctyne (DBCO)-branched primers to construct a PTEN gene nanovector (NP-PTEN) through branch-PCR. NP-PTEN showed the nanoscale structure with biocompatible size (84.7±11.2 nm) and retained the improved serum stability compared to linear DNA. When transfected into NCI-H1299 cancer cells, NP-PTEN could overexpress PTEN protein to restore PTEN functions through the deactivation of PI3K-AKT-mTOR signaling pathway to inhibit cell proliferation and induce cell apoptosis. The apoptosis rate of NCI-H1299 cancer cells could reach up to 54.5 %±4.6 % when the transfection concentration of NP-PTEN was 4.0 μg/mL. In mice bearing NCI-H1299 tumor xenograft intratumorally administrated with NP-PTEN, the average tumor volume and tumor weight was separately reduced by 61.7 % and 63.9 %, respectively, compared with the PBS group on the 18th day of administration. The anticancer efficacy of NP-PTEN in NCI-H1299 tumor xenograft suggests the promising therapeutic potential of branch-PCR assembled PTEN gene nanovectors in lung cancer gene therapy and also provided more opportunities to introduce two or more tumor suppressor genes as an all-in-one gene nanovector for multiple gene-based cancer gene therapy.

Anti-Cancer Properties of Clove Bud Essential Oil in Colon Cancer Cell Line

Colon cancer is a type of cancer that begins in the large intestine (colon). Its aggression is owing to late diagnosis so poor prognosis and higher mortality rate are reported. Colon cancer has become a thorny research region that requires more examination in cellular pathways involved in its emergency. Here we aim to investigate the possible anticancer properties of the clove oil as natural and popular oil in colon cancer CaCo-2 cells. Accordingly, cell viability rate and number of survived cells were monitored in response to the clove oil treatment compared with the black seed oil and DMSO-treatment. Lactate dehydrogenase (LDH) production was also considered as an indicator for necrotic event following treatment. The relative gene expression of Raf-1, MEK, and ERK was detected as proliferation effectors that linked to the expression profile of the tumor suppressor genes PTEN and TP53 using quantitative real-time PCR (qRT-PCR). Interestingly, here we identified Raf-1 pathway as a potential targeted singling by the clove oil resulted in controlling colon cancer cell proliferation. The current study elucidates the anticancer activities of the clove oil in colon cancer division through restoring the relative gene expression of PTEN and TP53 accompanied by over-production of interleukin 1 alpha (IL-1α) and IL-1β. Accordingly, treatment of the CaCo-2 cells with different concentrations of the clove oil increased programmed cells cell death (PCD) and inhibited the proliferation singling when compared with the black seed oil. Collectively, our results demonstrate that controlling of Raf-1 activity and PCD by clove oil treatment provide evidence for its anticancer effect in colon cancer cells.

Therapeutic prospects of ceRNAs in COVID-19.

Since the end of 2019, COVID-19 caused by SARS-CoV-2 has spread worldwide, and the understanding of the new coronavirus is in a preliminary stage. Currently, immunotherapy, cell therapy, antiviral therapy, and Chinese herbal medicine have been applied in the clinical treatment of the new coronavirus; however, more efficient and safe drugs to control the progress of the new coronavirus are needed. Long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs) may provide new therapeutic targets for novel coronavirus treatments. The first aim of this paper is to review research progress on COVID-19 in the respiratory, immune, digestive, circulatory, urinary, reproductive, and nervous systems. The second aim is to review the body systems and potential therapeutic targets of lncRNAs, miRNAs, and circRNAs in patients with COVID-19. The current research on competing endogenous RNA (ceRNA) (lncRNA-miRNA-mRNA and circRNA-miRNA-mRNA) in SARS-CoV-2 is summarized. Finally, we predict the possible therapeutic targets of four lncRNAs, MALAT1, NEAT1, TUG1, and GAS5, in COVID-19. Importantly, the role of PTEN gene in the ceRNA network predicted by lncRNA MALAT1 and lncRNA TUG1 may help in the discovery and clinical treatment of effective drugs for COVID-19.

The Effect of Atm Loss on Radiosensitivity of a Primary Mouse Model of Pten-Deleted Brainstem Glioma.

Simple SummaryBrainstem gliomas are deadly childhood brain tumors and new treatments are needed. The treatment meeting the standard of care is radiation therapy, but the tumors inevitably progress at some point after this treatment. One treatment strategy under preclinical investigation for brainstem gliomas is to inhibit the function of ataxia–telangiectasia mutated kinase (ATM), a master regulator of the cellular response to radiation therapy. ATM inhibition makes some tumors more sensitive to radiation therapy, but this may depend on the genetic makeup of the tumor. An important subset of brainstem gliomas harbor mutations in the PTEN gene or related genes. Here, we develop a genetically engineered mouse model of Pten-mutated brainstem glioma. We use genetic tools to test if ATM inactivation can enhance the efficacy of radiation therapy in this Pten-mutated brainstem glioma model. We find that ATM inactivation does not enhance the efficacy of radiation therapy for this model of Pten-mutated brainstem glioma. These findings indicate that PTEN mutational status should be considered in the design of inclusion criteria and correlative studies for future clinical trials of ATM inhibitors in brainstem glioma patients.Diffuse midline gliomas arise in the brainstem and other midline brain structures and cause a large proportion of childhood brain tumor deaths. Radiation therapy is the most effective treatment option, but these tumors ultimately progress. Inhibition of the phosphoinositide-3-kinase (PI3K)-like kinase, ataxia–telangiectasia mutated (ATM), which orchestrates the cellular response to radiation-induced DNA damage, may enhance the efficacy of radiation therapy. Diffuse midline gliomas in the brainstem contain loss-of-function mutations in the tumor suppressor PTEN, or functionally similar alterations in the phosphoinositide-3-kinase (PI3K) pathway, at moderate frequency. Here, we sought to determine if ATM inactivation could radiosensitize a primary mouse model of brainstem glioma driven by Pten loss. Using Cre/loxP recombinase technology and the RCAS/TVA retroviral gene delivery system, we established a mouse model of brainstem glioma driven by Pten deletion. We find that Pten-null brainstem gliomas are relatively radiosensitive at baseline. In addition, we show that deletion of Atm in the tumor cells does not extend survival of mice bearing Pten-null brainstem gliomas after focal brain irradiation. These results characterize a novel primary mouse model of PTEN-mutated brainstem glioma and provide insights into the mechanism of radiosensitization by ATM deletion, which may guide the design of future clinical trials.

Study to Identify the Signalling Cascade behind Expression Level of PTEN and RB1 gene in Breast Cancer

Study to Identify the Signalling Cascade behind Expression Level of PTEN and RB1 gene in Breast Cancer

Identification of Epigenetic Interactions between miRNA and Gene Expression as Potential Prognostic Markers in Bladder Cancer.

Purpose: To identify the role of a set of microRNAs and their target genes and protein expression levels in the pathogenesis of bladder cancer with a muscular invasion (T2–T4) and non-muscular invasion (T1). Methods: In 157 patients, bladder specimen was examined for the expression of a set of miRNAs including let-7a-5p, miRNA-449a-5p, miRNA-145-3P, miRNA-124-3P, miRNA-138-5p, and miRNA-23a-5p and their targeted genes; β-catenin, WNT7A, IRS2, FZD4, SOS1, HDAC1, HDAC2, HIF1α, and PTEN using the qRT-PCR technique. The prognostic effect of miRNAs and their targeted genes on cancer-specific survival (CSS) was evaluated in pT2–pT4 stages. Results: pT1 was found in 40 patients while pT2–4 was found in 117 patients. The expression of let-7a-5P, miR-124-3P, miR-449a-5P, and miR-138-5P significantly decreased in pT2–4 compared with pT1 (p < 0.001), in contrast, miR-23a-5P increased significantly in pT2–pT4 compared with pT1 (p < 0.001). Moreover, the expression of miR-145 did not show a significant change (p = 0.31). Higher expression levels of WNT7A, β-catenin, IRS2, FZD4, and SOS1 genes were observed in pT2–pT4 compared with pT1, whereas HDAC1, HDAC2, HIF1α, and PTEN genes were downregulated in pT2–pT4 compared with pT1. Lower CSS was significantly associated with lower expression of let-7a-5P, miR-124-3P, miR-449a-5P, and miR-138-5P. Higher expression of β-catenin, FZD4, IRS2, WNT7a, and SOS1 was significantly associated with worse CSS. In contrast, lower levels of HDAC1, HDAC2, HIF1α, and PTEN were associated with lower CSS. Conclusion: Our results support let-7a-5P, miR-124-3P, miR-138-5P, and their target genes can be developed as accurate biomarkers for prognosis in bladder cancer with a muscular invasion.

Thymoquinone Inhibits JAK/STAT and PI3K/Akt/ mTOR Signaling Pathways in MV4-11 and K562 Myeloid Leukemia Cells.

Constitutive activation of Janus tyrosine kinase-signal transducer and activator of transcription (JAK/STAT) and Phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathways plays a crucial role in the development of acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). Thymoquinone (TQ), one of the main constituents of Nigella sativa, has shown anti-cancer activities in several cancers. However, the inhibitory effect mechanism of TQ on leukemia has not been fully understood. Therefore, this study aimed to investigate the effect of TQ on JAK/STAT and PI3K/Akt/mTOR pathways in MV4-11 AML cells and K562 CML cells. FLT3-ITD positive MV4-11 cells and BCR-ABL positive K562 cells were treated with TQ. Cytotoxicity assay was assessed using WSTs-8 kit. The expression of the target genes was evaluated using RT-qPCR. The phosphorylation status and the levels of proteins involved in JAK/STAT and PI3K/Akt/mTOR pathways were investigated using Jess western analysis. TQ induced a dose and time dependent inhibition of K562 cells proliferation. TQ significantly downregulated PI3K, Akt, and mTOR and upregulated PTEN expression with a significant inhibition of JAK/STAT and PI3K/Akt/mTOR signaling. In conclusion, TQ reduces the expression of PI3K, Akt, and mTOR genes and enhances the expression of PTEN gene at the mRNA and protein levels. TQ also inhibits JAK/STAT and PI3K/Akt/mTOR pathways, and consequently inhibits proliferation of myeloid leukemia cells, suggesting that TQ has potential anti-leukemic effects on both AML and CML cells.

A progressive and refractory case of breast cancer with Cowden syndrome

BackgroundCowden syndrome is a rare autosomal-dominant disease with a high risk of malignant tumors of the breast, commonly caused by germline mutations in the PTEN gene. Most breast cancers related to Cowden syndrome showed typically a slow-growing and favorable clinical course. Here, we report a progressive case of triple-negative breast cancer in a patient who was diagnosed with Cowden syndrome.Case presentationA 35-year-old female with breast cancer was referred to our hospital. Histopathological examination of the tumor showed that it was triple-negative breast cancer with high proliferation marker. Preoperative positron emission tomography-computed tomography showed abnormal uptake in the left cerebellar hemisphere in addition to the right breast and axillary lymph node. Brain T2-weighted magnetic resonance imaging revealed hyperintense bands in the left cerebellar hemisphere lesion, which demonstrated a “tiger-stripe” appearance. The patient’s mother had died of endometrial cancer. Subsequently, she underwent genetic testing, leading to a diagnosis of Cowden syndrome with a pathogenic variant c.823_840del.18 at exon 8 in PTEN. She was treated with neoadjuvant chemotherapy of eribulin and cyclophosphamide followed by adriamycin and cyclophosphamide. However, her tumors increased after these treatments. She was immediately surgically treated and received adjuvant chemotherapy of capecitabine. Unfortunately, the cancer recurred in the lung nine months after surgery. We then administered paclitaxel and bevacizumab therapy, but the disease rapidly progressed. Consequently, the patient died due to breast cancer about three months after recurrence.ConclusionWe report an aggressive case of cancer with Cowden syndrome which was resistant to standard chemotherapy. Alteration of the phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin pathway due to inactivating PTEN protein may be associated with chemoresistance and serves as a candidate for therapeutic intervention in PTEN-related cancers.

PTEN Expression Was Significantly Associated with PD-L1 Score but Not with EBV Infection in Gastric Cancer.

PurposeGastric cancer (GC) remains a prevalent aggressive tumor with high morbidity and mortality globally. The identification of GC subtypes based on molecular features improved the prediction of prognosis and the selection of targeted therapies. PTEN is a characteristic tumor suppressor, while its association with different GC subtypes was unknown.Patients and MethodsThe cohort consisted of 248 patients diagnosed with gastric cancer who were hospitalized and received radical gastrectomy. In addition, PTEN gene expression matrix of STAD was retrieved from TCGA. The mRNA and protein levels of PTEN and PD-L1 were detected using qRT-PCR and IHC staining. Multivariate logistic regression and Kaplan–Meier analysis were used to examine the relationship between PTEN expression and clinical characteristics.ResultsIn our study, PTEN was downregulated in gastric tumors both in mRNA and protein levels. Its inactivation was closely linked to higher histological grade (P = 0.005), neural invasion (P = 0.012), depth of invasion (P = 0.021), lymph metastasis (P = 0.026), and TNM stage (P = 0.001) of GC in the present study. Moreover, according to the molecular subtypes, high PTEN expression was related to high TPS score of PD-L1 positively (P = 0.010) but was not associated with MSI and EBV infection. Further, TCGA data validated that PTEN was indeed correlated with histological grade and invasion depth and positively related to PD-L1 expression (R = 0.29, adjusted P < 0.001).ConclusionThe above results suggested that PTEN expression was a useful marker in gastric carcinogenesis and progression and in the selection of immunotherapy-based treatments for GC patients.

Retraction: PTEN gene silencing contributes to airway remodeling and induces airway smooth muscle cell proliferation in mice with allergic asthma.

[This retracts the article DOI: 10.21037/jtd.2017.12.104.].

In-silico designing of a potent ligand molecule against PTEN (Phosphatase and tensin homolog) implicated in Breast Cancer

Breast cancer has been attributed to be the second most common malignancy in females worldwide after skin cancer associated with a significantly high mortality rate. Tumor suppressor genes have an indispensable role in maintaining genomic integrity as well as cell cycle regulation. Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is one of the most frequently mutated human tumor suppressor genes, implicated in cell growth, survival, and suppressing tumor formation. As the tumor progresses to more advanced stages, genetic alterations tend to increase one such alteration is the mutation of the PTEN gene which is linked to programmed cell death and maintenance of cell cycle regulation. There is a syndrome known as Cowden syndrome associated with a high risk of breast cancer which is a result of an outcome of germline mutations in the PTEN gene. Loss of PTEN activity, either at the protein or genomic level, has been related to many primary and metastatic malignancies including breast cancer. This study focuses on developing a potential bioavailable ligand inhibitory molecule for PTEN, using a computer-aided drug design approach (CADD). A library of developed ligands consisting of 50 potential molecules was screened to find a potential candidate to be used for second generation drug development. Among them, LIG28 was adjudged as the most effective and potential PTEN inhibitor given its maximum binding affinity of ΔG -5.96Kcal/mole with a lower RMSD value. Carmer’s Rule of toxicity further revealed the compatibility and non-toxicity of the molecule. These observations underscore the importance of PTEN as a target in the development of tumorigenesis and the prognosis of breast cancer.

The Role of TSHR, PTEN and RASSF1A Promoters' Methylation Status for Non-Invasive Detection of Papillary Thyroid Carcinoma.

Aim: We investigated whether a difference exists between TSHR, PTEN and RASSF1A methylation status in plasma of subjects with papillary thyroid cancer (PTC). Methods: Peripheral blood samples were collected from 68 patients with PTC and 86 healthy controls (HC). Thyroid cancer tissue and corresponding adjacent normal tissue methylation levels were analyzed. DNA methylation level changes in TSHR, PTEN and RASSF1A genes were analyzed by quantitative methylation-sensitive polymerase chain reaction. Results: We observed that the methylation level of TSHR was significantly higher in the thyroid cancer tissue compared to adjacent normal tissue (p = 0.040). TSHR methylation levels in the PTC group plasma samples were significantly higher compared to HC (p = 0.022). After surgery, PTC plasma samples showed lower TSHR and PTEN methylation levels compared to the levels before surgery (p = 0.003, p = 0.031, respectively). The TSHR methylation level was significantly higher in PTC with larger tumor size (>2 cm) (p < 0.001), and lymph node metastases (p = 0.01), lymphovascular invasion (p = 0.02) and multifocality (p = 0.013) 0ROC analysis revealed that the TSHR methylation level provides high accuracy in distinguishing PTC from HC (p = 0.022, AUC of 0.616). Conclusion: TSHR methylation in peripheral blood samples is expected to be a sensitive and specific minimally invasive tool for the diagnosis of PTC, especially in combination with other diagnostic means.

Ubiquitous toxicity of Mercuric Chloride in target tissues and organs: Impact of Ubidecarenone and liposomal-Ubidecarenone STAT 5A/ PTEN /PI3K/AKT signaling pathways

BackgroundMercuric chloride (HgCl3) is categorized as class II B hazardous metal that is present in many occupational and environmental conditions. In the meantime, Hg exists in the environment in such an abundant manner, it is virtually impossible for humans to avoid exposure to different forms of Hg. In addition to environmental exposure, individuals may be exposed to Hg from dental amalgams, medicinal treatments and dietary sources. Nevertheless, Liposomal drug delivery system is a promising era in the field of Nano-medicine and have the advantageous of increasing drug bioavailability and retention phenomena in addition to targeting organ for all mentioned the present study was designed to investigate the hypothesis that messenger RNA gene expression of Signal transducer and activator of transcription- 5 A (STAT-5A), Phosphatase and tensin homolog (PTEN), phosphoinositol kinase (PI3K) and alpha serine/threonine-protein kinase (AKT) can trigger HgCl3 induced nephrotoxicity post Ubidecarenone and liposomal Ubidecarenone therapy. MethodsHgCl3 toxicity was induced in rats via a dose of 5 mg/kg BW for one week followed by Ubidecarenone and liposomal Ubidecarenone therapy in a dose of 10 & 3 mg/kg BW for one month, respectively. Then kidney function tests, Glutathione and gene expression for PI3K, AKT, PTEN and STAT-5A was investigated. ResultsHgCl3 intoxication significantly up regulated PI3K, AKT, PTEN and STAT-5A signaling pathways meanwhile, Ubidecarenone and liposomal- Ubidecarenone treatment significantly reduced PI3K, AKT, PTEN and STAT-5A gene expression post HgCl3 intoxication with the liposomal regimen revealing the most significant impact. Furthermore, renal toxicity was confirmed via monitoring urea and creatinine which were modulated post Ubidecarenone and liposomal-Ubidecarenone treatment. Wide evidence declared that mercuric S-conjugates of small endogenous thiols (such as Hcy, NAC and Cys) are probably the main transportable forms of Hg2+ to the kidneys thus reduced glutathione was investigated which reflected a significant down regulation post Hgcl3 toxicity. Conclusionliposomal drug delivery system including liposomal-Ubidecarenone can be considered as a prospective candidate for treating HgCl3 renal toxicity via modulating STAT-5A, PTEN, PI3K and AKT signaling pathways and via increasing retention time, bioavailability, shielding from macrophage recognition and targeting organs.

MicroRNA-29a-3p Regulates SH-SY5Y Cell Proliferation and Neurite Growth through Interaction with PTEN-PI3K/AKT/mTOR Signaling Pathway.

The effects of microRNA-29a-3p in the proliferation process of nerve cells are unclear. The purpose of this study is to delve into the regulatory role of microRNA-29a-3p, via interaction with phosphatase and tension homolog (PTEN), in the SH-SY5Y cell proliferation process. Different expressions of microRNA-29a-3p in the SH-SY5Y cells were constructed by transfected miRNA-29a-3p mimic and inhibitor. The effects of cell transfection and the mRNA expressions of PTEN, Akt, and mTOR were detected by qPCR. The expressions of PTEN, Akt, and mTOR protein and the phosphorylation levels of Akt and mTOR were examined using Western blotting. Nerve cell proliferation activity and neurite length of each group were measured and examined by the use of 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2Htetrazolium bromide (MTT), and morphological examination. We observed that the levels of PTEN mRNA and protein were distinctly decreased in the microRNA-29a-3p mimic group, but the expressions of the phosphorylated Akt and mTOR mRNA and protein were distinctly upregulated. In the transfected miRNA-29a-3p inhibitor SH-SY5Y cells, the expressions of miRNA-29a-3p were significantly suppressed; however, the expressions of PTEN gene and protein were significantly enhanced. The expressions of phosphorylated Akt and mTOR in the downregulated microRNA-29a-3p group distinctly were suppressed. The SH-SY5Y cell proliferation activity and neurite length in the upregulated microRNA-29a-3p group increased significantly. Our findings revealed that microRNA-29a-3p could enhance the proliferation activity of SH-SY5Y cells and promote neurite growth by inhibiting the expression of PTEN and regulating PI3K/Akt/mTOR signaling pathway.

S-palmitoylation of PCSK9 induces sorafenib resistance in liver cancer by activating the PI3K/AKT pathway.

Sorafenib is currently the first-line treatment for advanced hepatocellular carcinoma (HCC). However, sorafenib resistance remains a significant challenge. Aberrant AKT signaling activation is a crucial mechanism driving sorafenib resistance in HCC. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a vital role in antitumor immune responses. In this study, we demonstrate that aberrant PCSK9 upregulation promotes cell proliferation and sorafenib resistance in HCC by inducing AKT-S473 phosphorylation. After palmitoylation at cysteine 600, the binding affinity between PCSK9 and tensin homolog (PTEN) is dramatically increased, inducing lysosome-mediated PTEN degradation and subsequent AKT activation. We identify zinc finger DHHC-type palmitoyltransferase 16 (ZDHHC16) as a palmitoyltransferase that promotes PCSK9 palmitoylation at cysteine 600. We also develop a biologically active PCSK9-derived peptide that competitively inhibits PCSK9 palmitoylation, suppressing AKT phosphorylation and augmenting the antitumor effects of sorafenib in HCC.

Geniposide restricts angiogenesis in experimentary arthritis via inhibiting Dnmt1-mediated PTEN hypermethylation

Neovascularization in rheumatoid arthritis (RA) is a key bridge between malignant proliferative synovial tissue and pannus. In view of previous studies on the efficacy of Geniposide (GE) in experimentary arthritis, the purpose of this study was to investigate the possible mechanism of GE inhibiting angiogenesis by regulating the gene of phosphate and tension homology deleted on chromosome ten (PTEN). In this study, human umbilical vein endothelial cells (HUVEC) and adjuvant arthritis (AA) rat models were performed to research in vitro and in vivo. The results showed that GE treatment significantly reduced synovitis and angiogenesis in AA rats, which may be associated with the increased expression of PTEN with GE treatment. Meanwhile, the hypermethylation of PTEN accompanied by the over-expression of DNA methyltransferases (Dnmts) was demonstrated in TNF-α-induced HUVEC and AA rats. Knockdown of Dnmt1 by Dnmt1- siRNA significantly inhibited the tube formation of HUVEC in vitro. GE significantly restricted the angiogenesis of HUVEC by inhibiting DNA methylation, which was attributed to the down-regulation of Dnmt1 rather than Dnmt3a and Dnmt3b. The anti-angiogenesis effect of GE was further verified in AA model by the inhibition of Dnmt1. These results indicate that GE exhibited anti-angiogenesis effects in experimentary arthritis by inhibiting Dnmt1-mediated PTEN gene hypermethylation, which may brings new insights for the prevention and research of RA.

Expression Patterns of miR181a and miR30d in Patients with Breast Cancer.

Background:One of the important molecular pathways in breast cancer is the PTEN-PI3K-AKT pathway. Any change in the activity of the PTEN gene can alter the PI3K-AKT pathway. Moreover, there are subsets of genes and pathways their expression changes by post-transcriptional regulations. For instance, gene regulation alters by non-coding RNAs such as micro-RNAs as post-transcriptional regulators that prevent the expression of the target transcript. Therefore, it is essential to assess the related alterations in micro-RNA expression patterns to find out the possible causes of conversions in related transcripts and pathways such as the PTENPI3K-AKT pathway in breast cancer.Methods:To determine the expression level of miR-181a and miR-30d in 30 breast tumor samples and 30 adjacent normal samples, the RNA extraction, and cDNA synthesis was performed by RiboEx (GeneAll, Korea). Finally, the Real-Time PCR method was used for quantitative analysis of the expression levels of these miRNAs. all the experimental part of the project in done at Islamic Azad University in 2017.Results:After analyzing comparisons in the expression level of miR-181a and miR-30d in tumor and normal tissues, there was a significant increase in the expression level of miR-181a in tumor samples compared with normal samples. Moreover, the expression level of miR-30d in tumor samples reported a significant decrease in comparison with normal samples (P<0.05).Conclusion:Upregulation of miR-181a may affect the transcription of the PTEN gene resulting in the cell progress to cancer. The Downregulation of miR-30d may also lead to cancer cell growth, due to a reduction in the affecting on the CREB gene transcript.