Publications by authors named "Xun Jin"

78 Publications

LncRNA HAS2-AS1 Promotes Glioblastoma Proliferation by Sponging miR-137.

Front Oncol 2021 20;11:634893. Epub 2021 May 20.

Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China.

GBM (Glioblastoma multiform) is the most malignant tumor type of the central nervous system and has poor diagnostic and clinical outcomes. LncRNAs (Long non-coding RNAs) have been reported to participate in multiple biological and pathological processes, but their underlying mechanism remains poorly understood. Here, we aimed to explore the role of the lncRNA HAS2-AS1 (HAS2 antisense RNA 1) in GBM. GSE103227 was analyzed, and qRT-PCR was performed to measure the expression of HAS2-AS1 in GBM. FISH (Fluorescence hybridization) was performed to verify the localization of HAS2-AS1. The interaction between HAS2-AS1 and miR-137 (microRNA-137) was predicted by LncBook and miRcode followed by dual-luciferase reporter assays, and the relationships among HAS2-AS1, miR-137 and LSD1 (lysine-specific demethylase 1) were assessed by WB (western blot) and qRT-PCR. Colony formation and CCK-8 (cell counting kit-8) assays were performed as functional tests. In vivo, nude mice were used to confirm the function of HAS2-AS1. HAS2-AS1 expression was upregulated in GBM cell lines, and HAS2-AS1 was localized mainly in the cytoplasm. , high HAS2-AS1 expression promoted proliferation, and knockdown of HAS2-AS1 significantly inhibited proliferation. Furthermore, HAS2-AS1 functioned as a ceRNA (competing endogenous RNA) of miR-137, leading to the disinhibition of its downstream target LSD1. The miR-137 level was downregulated by HAS2-AS1 overexpression and upregulated by HAS2-AS1 knockdown. In a subsequent study, LSD1 expression was negatively regulated by miR-137, while miR-137 reversed the LSD1 expression levels caused by HAS2-AS1. These results were further supported by the nude mouse tumorigenesis experiment; compared with xenografts with high HAS2-AS1 expression, the group with low levels of HAS2-AS1 exhibited suppressed proliferation and better survival. We conclude that lncRNA HAS2-AS1 promotes proliferation by functioning as a miR-137 decoy to increase LSD1 levels and thus might be a possible biomarker for GBM.
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http://dx.doi.org/10.3389/fonc.2021.634893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173206PMC
May 2021

AMOTL2‑knockdown promotes the proliferation, migration and invasion of glioma by regulating β‑catenin nuclear localization.

Oncol Rep 2021 07 26;46(1). Epub 2021 May 26.

Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China.

Glioblastoma multiforme (GBM) is the most prevalent type of malignant cancer in the adult central nervous system; however, its mechanism remains unclear. Angiomotin‑like 2 (AMOTL2) is a member of the motin family of angiostatin‑binding proteins. It has been reported as an oncogene in cervical and breast cancer, but its association with glioma remains unknown. The aim of the present study was to investigate AMOTL2‑regulated processes in glioma cell lines using extensive assays and certain bioinformatics tools. These results revealed that AMOTL2 was downregulated in high‑grade glioma cells and tissues, with patients with glioma exhibiting a high AMOTL2 expression having a higher survival rate. The results of the glioma cell phenotype experiment showed that AMOTL2 suppressed GBM proliferation, migration and invasion. In addition, immunoblotting, co‑immunoprecipitation and immunofluorescence assays demonstrated that AMOTL2 could directly bind to β‑catenin protein, the key molecule of the Wnt signaling pathway, and regulate its downstream genes by regulating β‑catenin nuclear translocation. In conclusion, the present study demonstrated that AMOTL2 inhibited glioma proliferation, migration and invasion by regulating β‑catenin nuclear localization. Thus, AMOTL2 may serve as a therapeutic target to further improve the prognosis and prolong survival time of patients with glioma.
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http://dx.doi.org/10.3892/or.2021.8090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165599PMC
July 2021

Amlexanox Enhances Temozolomide-Induced Antitumor Effects in Human Glioblastoma Cells by Inhibiting IKBKE and the Akt-mTOR Signaling Pathway.

ACS Omega 2021 Feb 5;6(6):4289-4299. Epub 2021 Feb 5.

Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China.

Temozolomide (TMZ), as the first-line chemotherapeutic agent for the treatment of glioblastoma multiforme (GBM), often fails to improve the prognosis of GBM patients due to the quick development of resistance. The need for more effective management of GBM is urgent. The aim of this study is to evaluate the efficacy of combined therapy with TMZ and amlexanox, a selective inhibitor of IKBKE, for GBM. We found that the combined treatment resulted in significant induction of cellular apoptosis and the inhibition of cell viability, migration, and invasion in primary glioma cells and in the human glioma cell line, U87 MG. As expected, TMZ enhanced the expression of -AMPK and amlexanox led to the reduction of IKBKE, with no impact on -AMPK. Furthermore, we demonstrated that compared to other groups treated with each component alone, TMZ combined with amlexanox effectively reversed the TMZ-induced activation of Akt and inhibited the phosphorylation of mTOR. In addition, the combination treatment also clearly reduced in vivo tumor volume and prolonged median survival time in the xenograft mouse model. These results suggest that amlexanox sensitized the primary glioma cells and U87 MG cells to TMZ at least partially through the suppression of IKBKE activation and the attenuation of TMZ-induced Akt activation. Overall, combined treatment with TMZ and amlexanox may provide a promising possibility for improving the prognosis of glioblastoma patients in clinical practice.
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http://dx.doi.org/10.1021/acsomega.0c05399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906592PMC
February 2021

Effects of sEA on Slow Transit Constipation through the Microbiota-Gut-Brain Axis in Rats.

Evid Based Complement Alternat Med 2020 14;2020:8828846. Epub 2020 Dec 14.

Oncology Business Development Department, Hutchison MediPharma Limited, Shanghai 201203, Building 7, 898 Halei Road Zhangjiang Hi-Tech Park Pudong, China.

To investigate the effect of sacral electroacupuncture (sEA) on the microbiota-gut-brain axis in the treatment of slow transit constipation, this study established a drug-induced model of slow transit constipation in rats and carried out sEA at the Baliao acupoints (BL31-BL34). On the 14th day of the therapeutic period (24 h fecal pellets), the aquaporin 3 (AQP3), 5-hydroxytryptamine (5-HT), and substance (SP) transcripts from the distal colon and hypothalamus were analyzed. 16S rDNA has been widely used to analyze the diversity of the microbial communities. Therefore, in the present study, changes in the intestinal microbiota were analyzed by 16S rDNA gene sequencing. The results showed that sEA significantly increased the number of fecal pellets and the water content in the feces and reduced the reabsorption of intestinal water in 24 h. sEA also upregulated the level of SP mRNA expression in the distal colon and the hypothalamus, but downregulated the level of 5-HT mRNA expression in the distal colon. Moreover, sEA improved the Bacteroidetes to Firmicutes (B/F) ratio, which is beneficial to the general structure of the intestinal microflora. Our findings suggested that the microbiota-gut-brain axis constitutes a crucial pathological basis in the development of slow transit constipation. sEA improved the slow transit constipation by regulating the balance of the microbiota-gut-brain axis.
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http://dx.doi.org/10.1155/2020/8828846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755465PMC
December 2020

Methotrexate-loaded tumour-cell-derived microvesicles can relieve biliary obstruction in patients with extrahepatic cholangiocarcinoma.

Nat Biomed Eng 2020 07 6;4(7):743-753. Epub 2020 Jul 6.

Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Most patients with cholangiocarcinoma (CCA) develop extrahepatic malignant biliary obstructions, which require palliative drainage to normalize bilirubin levels and to improve the patients' overall survival. Here, we report that the infusion of methotrexate-containing plasma-membrane microvesicles derived from apoptotic human tumour cells into the bile-duct lumen of patients with extrahepatic CCA mobilized and activated neutrophils and relieved biliary obstruction in 25% of the patients. Neutrophil recruitment by the microvesicles was associated with an increase in uridine diphosphate glucose and complement C5, and led to the degradation of the stromal barrier of CCA. The microvesicles induced pyroptosis of CCA cells through a gasdermin E-dependent pathway, and their intracellular contents released upon CCA-cell death activated patient-derived macrophages into producing proinflammatory cytokines, which attracted a secondary wave of neutrophils to the tumour site. Our findings suggest a possible treatment for the alleviation of obstructive extrahepatic CCA with few adverse effects, and highlight the potential of tumour-cell-derived microvesicles as drug carriers for antitumour therapies.
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http://dx.doi.org/10.1038/s41551-020-0583-0DOI Listing
July 2020

The Protective Effect of Pre-Moxibustion on Reproductive Hormones Profile of Rats with Tripterygium Glycosides-Induced Ovarian Damage.

Complement Med Res 2020 11;27(6):401-409. Epub 2020 Jun 11.

Second Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China.

Background: Acupuncture and moxibustion have been proven to be conducive to improving the ovarian reserve. However, the mechanism of pre-moxibustion on Tripterygium glycosides (TG)-induced ovarian damage has not been previously reported.

Method: Female rats were randomly divided into 5 groups: control, model (75 mg/kg TG, 14 days), preventive moxibustion 1 (PM1, receiving moxibustion for 4 weeks before TG administration), preventive moxibustion 2 (PM2, receiving moxibustion for 2 weeks before TG administration and another 2 weeks during TG administration), and preventive moxibustion 3 (PM3, receiving 4 weeks of moxibustion during TG administration). The estrous cycle of the animal was recorded after TG administration. Rats were sacrificed 14 days after TG administration. The reproductive hormones profiles in serum, ovary, and hypothalamic tissues were analyzed.

Result: Pre-moxibustion could revert abnormal estrous cycles, relieve follicle damage, and improve abnormal secretion of reproductive hormones resulting from ovarian damage. However, both PM2 and PM3 were more effective than PM1. In addition, PM2 disclosed more advantages in regulating reproductive hormones abnormalities, while PM3 performed better in follicular development.

Conclusion: In combination, the findings of this study suggest that pre-moxibustion is effective in protecting the ovary from damage in TG-induced ovarian damage rats. But different time points correspond to different modulation targets and mechanisms.
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http://dx.doi.org/10.1159/000506434DOI Listing
June 2020

ACT001 reduces the expression of PD-L1 by inhibiting the phosphorylation of STAT3 in glioblastoma.

Theranostics 2020 1;10(13):5943-5956. Epub 2020 May 1.

Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China.

ACT001, which is derived from an ancient anti-inflammatory drug, has been shown to cross the blood-brain barrier in preclinical studies and has demonstrated anti-glioblastoma (GBM) activity in clinical trials. However, its pharmacological potential for anti-GBM immune response modulation remains unclear. The chemical structure of ACT001 indicates that it may bind to STAT3 and thus modulate antitumor immune response. Bioinformatics and immunohistochemistry (IHC) were used to assess STAT3 and PD-L1 expression in gliomas. Western blotting, RT-PCR and immunofluorescence were used to detect PD-L1 and p-STAT3 expression in glioma cells exposed to ACT001. Chromatin immunoprecipitation, an ACT001-Biotin probe, and a dual-luciferase reporter assay were used to detect direct modulation. The efficacy of ACT001 was evaluated in GL261 murine glioma model. Survival analyses were conducted using the log-rank (Mantel-Cox) test. Bioinformatic analysis of 1,837 samples from 4 public glioma datasets showed that STAT3 mRNA expression was correlated with the degree of malignancy and therapeutic resistance and that STAT3 mRNA expression was related to immunosuppression, leukocyte infiltration, and PD-L1 expression. IHC staining of 53 tissue samples confirmed that relatively high phosphorylated STAT3 and PD-L1 protein expression was associated with a relatively advanced World Health Organization (WHO) glioma grade. Next, we confirmed that ACT001 treatment reduced PD-L1 expression and STAT3 phosphorylation. An ACT001-biotin probe was used to verify that ACT001 bound to STAT3. We also demonstrated that STAT3 bound to the PD-L1 promoter. The inhibition of PD-L1 expression and STAT3 phosphorylation by ACT001 could be rescued by STAT3 overexpression. Additionally, ACT001 inhibited GBM growth and decreased PD-L1 expression . The expression of the M2 markers CD206 and CD163 was decreased, while that of the antitumor immune markers iNOS and IFNγ was increased by ACT001 . Our results demonstrate that STAT3 plays a key role in immunosuppression of glioma and is inhibited by ACT001. ACT001 inhibits PD-L1 transcription and modulates anti-tumor immune response in glioma bearing mice. These findings will help us to understand the mechanism of ACT001 in GBM therapy.
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http://dx.doi.org/10.7150/thno.41498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254983PMC
May 2020

Loss of core fucosylation enhances the anticancer activity of cytotoxic T lymphocytes by increasing PD-1 degradation.

Eur J Immunol 2020 11 3;50(11):1820-1833. Epub 2020 Sep 3.

College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China.

As an immune checkpoint, programmed cell death 1 (PD-1) and its ligand (PD-L1) pathway plays a crucial role in CD8 cytotoxic T lymphocytes (CTL) activation and provides antitumor responses. The N-glycans of PD-1 and PD-L1 are highly core fucosylated, which are solely catalyzed by the core fucosyltransferase (Fut8). However, the precise biological mechanisms underlying effects of core fucosylation of PD-1 and PD-L1 on CTL activation have not been fully understood. In this study, we found that core fucosylation was significantly upregulated in lung adenocarcinoma. Compared to those of Fut8 OT-I mice, the lung adenocarcinoma formation induced by urethane was markedly reduced in Fut8 OT-I mice. De-core fucosylation of PD-1 compromised its expression on Fut8 CTL, resulted in enhanced Fut8 CTL activation and cytotoxicity, leading to more efficient tumor eradication. Indeed, loss of core fucosylation significantly enhanced the PD-1 ubiquitination and in turn led to the degradation of PD-1 in the proteasome. Our current work indicates that inhibition of core fucosylation is a unique strategy to reduce PD-1 expression for the antilung adenocarcinoma immune therapy in the future.
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http://dx.doi.org/10.1002/eji.202048543DOI Listing
November 2020

[Effect of electroacupuncture on tissue elasticity and expression of muscular MyoD and myogenin in rats with acute gastrocnemius contusion].

Zhen Ci Yan Jiu 2020 Apr;45(4):287-92

Department of Acupuncture and Moxibustion, First Affiliated Hospital of Nanjing Medical University, Nanjing 210000.

Objective: To observe the effect of electroacupuncture (EA) at "Ashi" acupoint and "Kunlun" (BL60) on elastic modulus, histopathological changes and expression of myogenic regulatory factors in gastrocnemius(GM) contusion rats, so as to explore the therapeutic effect of local acupoint selection and acupoint selection along channel.

Methods: Male SD rats were randomly divided into blank control (=5), model (=15), Ashi-point (=15) and BL60 (=15) groups. The acute GM contusion model was established by striking (free falling) the GM with a homemade hitter. EA (0.5 to 1.0 mA, 2 Hz/10 Hz) was applied to Ashi-point (local focus) and BL60 for 30 min 24 h after muscle injury. The elasticity maximum (Emax) of gastrocnemius muscle was measured by using an ultrasonic device. Histopathological changes were observed after H.E. stain, and the number of Myogenic differentiation(MyoD)- and Myogenin (MyoG)-positive cells was detected by using immunohistochemistry.

Results: After mdeling, the Emax value of GM was significantly increased from the 3 h to 7 day in comparison with pre- injury of muscle (<0.05), and was markedly increased on the 3 day and obviously lower on day 7 in the Ashi-point group than in the model group (<0.05). The numbers of MyoD- and MyoG-positive cells of GM were significantly increased on day 7 in the model group than in the blank control group (<0.05), and both further increased in Ashi-point on day 3 and 5, and MyoG-positive cells further increased in BL60 group on day 5 and in Ashi-point group on day 7 relevant to the model group(<0.05). The therapeutic effect of EA-Ashi-point was apparently superior to that of BL60 in up-regulating Emax on day 3 and in up-regulating the number of MyoD-positive cells on day 3 and 5 (<0.05). H.E. stain showed disordered arrangement of muscle fibers, infiltration of inflammatory cells, increase of intercellular space, and edema on day 3 after modeling (which was milder in the Ashi-point group); and gradual fusion and thickening of new born muscle fibers with obvious connective tissue hyperplasia converged to the lesioned region on day 7 in the model group (convergence of new born muscle cells to the lesion region in both EA groups, and more complete tissues in the Ashi-point group).

Conclusion: EA of Ashi-point and BL60 can up-regulate the expression of myogenic regulatory factors MyoD and MyoG of GM tissue in GM contusion rats, which may contribute to its function in promoting recovery of muscle elasticity. The role of EA-Ashi-point is superior to that of EA-BL60.
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http://dx.doi.org/10.13702/j.1000-0607.190361DOI Listing
April 2020

Integrated miRNA-seq analysis reveals the molecular mechanism underlying the effect of acupuncture on endometrial receptivity in patients undergoing fertilization: embryo transplantation.

3 Biotech 2020 Jan 27;10(1). Epub 2019 Nov 27.

1College of Acupuncture and Tuina, Nanjing University of Chinese Medicine, Nanjing, 210023 Jiangsu China.

Endometrial receptivity (ER) is the main factor affecting in vitro fertilization (IVF) and embryo transplantation. Previous studies have shown that acupuncture might be useful for increasing ER. However, the underlying microRNA (miRNA) molecular mechanisms deserve to be further elucidated. In this study, we performed small RNA sequencing of endometrial samples from infertile women who either underwent acupuncture therapy or did not. Differentially expressed microRNAs (DEmiRNAs) were identified and used to predict target genes. Then, the functional and pathway were analyzed for the target genes. Moreover, quantitative reverse transcription PCR (qRT-PCR) was performed to validate the RNA-seq results. Finally, the miRNA-gene network was conducted by Cytoscape. A total of 39 DEmiRNAs were identified between the acupuncture group and the control group. The functional enrichment analysis suggested that the target genes of the DEmiRNAs were significantly enriched in GO biological process (BP) terms associated with transcription, such as regulation of DNA-templated transcription and positive regulation of DNA-templated transcription. The pathway analysis showed that DEmiRNAs might be involved in acupuncture therapy via Endocytosis, Axon guidance, Oxytocin signaling, the Hippo pathway, and Estrogen signaling pathways. Significant downregulation of hsa-miR-449a and hsa-miR-449b-3p, and significant upregulation of hsa-miR-3135b and hsa-miR-345-3p in the RNA-seq results were validated by qRT-PCR. Besides, these four DEmiRNAs and their 34 target genes conducted a miRNA-gene network. Our results predict that hsa-miR-449a, hsa-miR-3135b and hsa-miR-345-3p may underly mechanisms by which acupuncture therapy help increase ER and promote endometrium receptivity in preparation for in vitro fertilization and embryo transplantation.
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http://dx.doi.org/10.1007/s13205-019-1990-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879696PMC
January 2020

Long Non-Coding RNA HOTAIR Modulates KLF12 to Regulate Gastric Cancer Progression via PI3K/ATK Signaling Pathway by Sponging miR-618.

Onco Targets Ther 2019 27;12:10323-10334. Epub 2019 Nov 27.

Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, Henan Province, People's Republic of China.

Purpose: Long non-coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) has been reported to dysregulate in many tumors. However, the mechanism of HOTAIR was rarely reported in GC.

Methods: The levels of HOTAIR, microRNA-618 (miR-618) and Krueppel-like factor 12 (KLF12) in GC tissues and cells were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The cell viability and apoptotic rate were assessed via cell counting kit-8 (CCK-8) assay and flow cytometry, respectively. The migrating and invading abilities were tested by Transwell assay. The protein levels of KLF12, p-PI3K, PI3K, p-ATK and ATK were measured by Western blot assay. These interactions between miR-618 and HOTAIR or KLF12 were predicted by DIANA tools, and then, dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were conducted to validate these interactions. Besides, the xenograft tumor experiment was performed to further verify the roles of HOTAIR in GC.

Results: The levels of HOTAIR and KLF12 were significantly upregulated and the level of miR-618 was strikingly downregulated in GC tissues and cells. miR-618 was verified as a direct target of HOTAIR or KLF12. HOTAIR silencing blocked GC progression and PI3K/ATK signaling pathway by sponging miR-618 and also restrained xenograft tumor growth in vivo. miR-618 inhibited GC progression and PI3K/ATK signaling pathway by targeting KLF12. Mechanistically, HOTAIR modulated KLF12 expression by sponging miR-618 in GC cells.

Conclusion: These data unraveled that HOTAIR promoted GC progression through PI3K/ATK signaling pathway via miR-618/KLF12 axis.
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http://dx.doi.org/10.2147/OTT.S223957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885573PMC
November 2019

[Effect of moxibustion pretreatment at different time on ovarian function in rats with dimini-shed ovarian reserve].

Zhen Ci Yan Jiu 2019 Nov;44(11):817-21

Department of Acupuncture-moxibustion, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029.

Objective: To observe the effect of moxibustion pretreatment at different time on serum hormone levels in diminished ovarian reserve (DOR) rats, so as to explore its protective mechanisms.

Methods: Forty female SD rats were randomly divided into control, model, moxibustion-1 (moxibustion was given 4 weeks before modeling), moxibustion-2 (moxibustion was given 2 weeks before modeling and 2 weeks from the 1st day on after modeling ) and moxibustion-3 (moxibustion was given 4 weeks from the 1st day on after modeling) groups (=8 rats in each group). The DOR model was established by gavage of Tripterygium Glycosides (75 mg/kg) once daily for 14 days. Grain-moxibustion was applied to "Shenshu" (BL23) and "Guanyuan" (CV4) for 7 cones, 5 times a week for 4 weeks. The body weight and the ovary weight were recorded for calculating the ovarian index. The levels of serum anti-mullerian hormone (AMH), follicle stimulating hormone (FSH), estradiol (E2), androgen (T) and dehydroepiandrosterone (DHEA) were detected by ELISA.

Results: After modeling, ovarian index and serum AMH levels were obviously decreased (<0.05), and the levels of serum FSH, E2, T and DHEA were significantly increased in contrast with the control group (<0.05). Following intervention and compared with the model group, the serum FSH and DHEA levels of each moxibustion group were significantly reduced (<0.05), the AMH levels significantly increased and E2 and T contents significantly decreased in the moxibustion-2 and moxibustion-3 groups (<0.05). The serum FSH, E2 and T contents in moxibustion-2 group were obviously lower than those of the moxibustion-1 and moxibustion-3 groups (<0.05).

Conclusion: Moxibustion pre-treatment can improve ovarian reserve function in DOR rats, while the effect is different with different intervention time, and the best intervention time is pre-occurrence and early stage of DOR.
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http://dx.doi.org/10.13702/j.1000-0607.190220DOI Listing
November 2019

Whole Transcriptome Sequencing Reveals How Acupuncture and Moxibustion Increase Pregnancy Rate in Patients Undergoing In Vitro Fertilization-Embryo Transplantation.

Biomed Res Int 2019 28;2019:4179617. Epub 2019 May 28.

The Second Clinical College, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China.

Background: In vitro fertilization and embryo transfer (IVF-ET) technology has been widely used in the therapy of refractory infertility. Previous studies showed that acupuncture can effectively increase the clinical pregnancy rate of IVF-ET. However, the molecular mechanism is unknown.

Materials And Methods: In this study, we performed whole transcriptome sequencing for endometrial samples from infertile women who underwent acupuncture and moxibustion therapy or not. Differentially expressed noncoding RNAs (ncRNAs) and mRNAs were identified and their functions were predicted. Besides, a competitive endogenous RNA network was constructed to further interpret the molecular mechanism of acupuncture and moxibustion therapy on infecund patients. In addition, real-time PCR was applied to validate the RNA-seq results.

Results: We identified 317 differentially expressed mRNAs and 82 ncRNAs in acupuncture and moxibustion therapy group compared with control group. Functional enrichment analysis suggested that these genes were significantly enriched in GO-BP terms associated with cellular transport, such as ATP hydrolysis coupled proton transport, vacuolar acidification, transferrin transport, and proton transport and metabolic process, including small molecule metabolic process and metabolic process. Pathway enrichment analysis enriched 11 terms, including oxidative phosphorylation, synaptic vesicle cycle, mineral absorption, and metabolic pathways. Four of five selected differentially expressed genes were validated by real-time PCR.

Conclusion: Our results suggested that acupuncture and moxibustion therapy might increase the pregnancy rate of patients undergoing IVF-ET by the regulation of ncRNAs.
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http://dx.doi.org/10.1155/2019/4179617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558619PMC
December 2019

Circular RNA sequencing reveals the molecular mechanism of the effects of acupuncture and moxibustion on endometrial receptivity in patients undergoing infertility treatment.

Mol Med Rep 2019 Aug 14;20(2):1959-1965. Epub 2019 Jun 14.

The Second Clinical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China.

The present study aimed to determine the profile of differentially expressed circular RNAs (circRNAs) in infertile patients treated with acupuncture and moxibustion and verify the role of acupuncture and moxibustion in altering endometrial receptivity (ER). High‑throughput RNA sequencing and bioinformatics analysis of samples from six pairs of patients treated with or without acupuncture and moxibustion were conducted. The reliability of high‑throughput RNA sequencing was validated using reverse transcription‑quantitative PCR. The most significant circRNA functions and pathways were selected by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. A circRNA‑miR‑mRNA interaction network was constructed to determine the connection between circRNAs, microRNAs (miRs), and mRNAs. High‑throughput RNA sequencing identified 2,653 circRNAs. A total of 86 circRNAs was differentially expressed, of which 57 were upregulated and 29 were downregulated, between the acupuncture and moxibustion group and the control group. In the GO analysis, the identified BP terms were chromatin modification, positive regulation of transcription from RNA polymerase II promoter involved in unfolded protein response, oxidative DNA demethylation, regulation of transcription from RNA polymerase II promoter in response to hypoxia, and regulation of smooth muscle cell differentiation. The identified CC terms were nucleoplasm, nucleolus, nucleus, histone acetyltransferase complex, and annulate lamellae. The identified MF terms were methylcytosine dioxygenase activity, chromatin binding, zinc ion binding, histone binding, and protein binding. In the KEGG pathway analysis, the identified pathways were protein processing in endoplasmic reticulum, degradation of aromatic compounds, shigellosis, mTOR signaling pathway, bacterial invasion of epithelial cells, and prostate cancer. Circ‑SFMBT2, circ‑BACH1, and circ‑LPAR1 were significantly upregulated (P<0.05) and associated with numerous miRs and mRNAs. Acupuncture and moxibustion could impact ER by regulating the expression of circRNAs.
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http://dx.doi.org/10.3892/mmr.2019.10386DOI Listing
August 2019

Ly6G inflammatory cells enable the conversion of cancer cells to cancer stem cells in an irradiated glioblastoma model.

Cell Death Differ 2019 Oct 25;26(10):2139-2156. Epub 2019 Feb 25.

Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.

Most glioblastomas frequently recur at sites of radiotherapy, but it is unclear if changes in the tumor microenvironment due to radiotherapy influence glioblastoma recurrence. Here, we demonstrate that radiation-induced senescent glioblastoma cells exhibit a senescence-associated secretory phenotype that functions through NFκB signaling to influence changes in the tumor microenvironment, such as recruitment of Ly6G inflammatory cells and vessel formation. In particular, Ly6G cells promote conversion of glioblastoma cells to glioblastoma stem cells (GSCs) through the NOS2-NO-ID4 regulatory axis. Specific inhibition of NFκB signaling in irradiated glioma cells using the IκBα super repressor prevents changes in the tumor microenvironment and dedifferentiation of glioblastoma cells. Treatment with Ly6G-neutralizing antibodies also reduces the number of GSCs and prolongs survival in tumor-bearing mice after radiotherapy. Clinically, a positive correlation exists between Ly6G cells and the NOS2-NO-ID4 regulatory axis in patients diagnosed with recurrent glioblastoma. Together, our results illustrate important roles for Ly6G inflammatory cells recruited by radiation-induced SASP in cancer cell dedifferentiation and tumor recurrence.
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http://dx.doi.org/10.1038/s41418-019-0282-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748155PMC
October 2019

Correlation Network Analysis Provides Important Modules and Pathways for Human Hyperlipidemia.

Crit Rev Eukaryot Gene Expr 2019 ;29(5):437-448

Yang Zhou Hospital of Traditional Chinese Medicine, Yangzhou 225000, China.

Hyperlipidemia casts great threats to humans around the world. The systemic co-expression and function enrichment analysis for this disease is limited to date. This study was to identify co-expression modules to explore hyperlipidemia-associated functional pathways. Gene expression data of human hyperlipidemia (GSE17170) were downloaded from the Gene Expression Omnibus (GEO) database. We evaluated the top 3,000 genes with the highest average expression, with which the co-expression modules were constructed in weighted correlation network analysis (WGC-NA).Cluster analysis was then applied to visualize the interaction relationships of these modules. By gene ontology (GO) and KEGG functional enrichment analysis, we finally investigated the function enrichment of co-expression genes from important modules in the Database for Annotation, Visualization, and Integrated Discovery (DAVID) database (https:// david.ncifcrf.gov/summary.jsp).15 Thirteen co-expression modules were constructed for 3,000 genes in the 70samples. Interaction relationships of hub genes between pairwise modules showed high confidence. In functional enrichments of the co-expression modules, genes in Modules 3 and 4 were significantly enriched in biological processes and pathways that are associated with ubiquitination-for example, G0:0016567 (protein ubiquitination) and hsa04120 (ubiquitin-mediated proteolysis). We inferred these two modules as key modules associated with hyperlipidemia. Additionally, G0:0098609 (cell-cell adhesion) was enriched in four modules, suggesting an important function in hyperlipidemia. In conclusion, Protein ubiquitination may play important roles in human hyperlipidemia. All the discoveries made in this study enrich understanding of the pathogenesis of hyperlipidemia and might contribute much to the development of diagnosis and outcome evaluation of this disease.
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http://dx.doi.org/10.1615/CritRevEukaryotGeneExpr.2019026444DOI Listing
August 2020

[Symptom distribution of female pelvic floor dysfunction patients with constipation as chief complaint].

Zhonghua Wei Chang Wai Ke Za Zhi 2018 Jul;21(7):798-802

Department of Colorectal Surgery of Chinese Medicine, Nanjing University of Traditional Chinese Medicine, Nanjing 210001, China.

Objective: To observe the multiple symptom distribution, severity and quality of life of female pelvic floor dysfunction(FPFD) patients with constipation as chief complaint.

Methods: One hundred FPFD patients with constipation as chief complaint from Speciaty Outpatient Clinic, Pelvic Floor Center of Nanjing Municipal Hospital of Traditional Chinese Medicine between September 2015 and February 2017 were retrospectively enrolled in this study. A comprehensive medical history questionnaire survey and systematical evaluation of severity and quality of life of these patients with constipation was conducted. Constipation scoring system scale (CSS) and patient-assessment of constipation quality of life questionnaire (PAC-QOL) were applied to evaluate the constipation. Other scales included: (1)pain visual analogue scale (VAS) and short form-36 questionnaire (SF-36): if combined with chronic functional anal rectal pain; (2) international consultation on incontinence questionnaire-short form (ICIQ-SF) and urinary incontinence quality of life questionnaires (I-QOL):if combined with urinary incontinence; (3) fecal incontinence severity score scale (Wexner-FIS) and fecal incontinence quality of life questionnaire (FI-QOL):if combined with fecal incontinence.

Results: The mean age of 100 FPFD patients was (57.9±13.9) (24-89) years and the mean disease course was (7.0±8.2)(0.5-40.0) years. Seventy-five cases (75%) were complicated with anal pain, 70 with urinary incontinence, 37 with rectocele, 19 with nocturia, 11 with urinary frequency, 10 with defecation incontinence. Complication with only one symptom was observed in 20 cases (20%), and with two or more symptoms was observed in 80 cases (80%). Pelvic floor relaxation syndrome patients were dominant (58 cases, 58%). The severity of constipation (CSS) was 6-22 (13.89±3.79) points and the quality of life (PAC-QOL) was 45-133 (87.13±18.57) points in FPFD patients. VAS and SF-36 of patients combined with chronic functional anal rectal pain were 1-8 (3.0±1.9) points and 14.4-137.0(71.5±31.4) points respectively. ICIQ-SF and I-QOL of patients combined with urinary incontinence were 1-17 (6.1±3.6) points and 52-110 (90.0±15.8) points respectively. Wexner-FIS and FI-QOL of patients combined with fecal incontinence were 1-11 (4.4±3.0) points and 52-116 (83.4±23.3) points respectively.

Conclusions: The symptoms of FPFD patients with constipation as chief complaint are complex. They are mainly complicated with anal diseases, then urinary incontinence, and mostly with more than 2 symptoms. Their quality of life is poor.
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July 2018

Fibrin Stiffness Mediates Dormancy of Tumor-Repopulating Cells via a Cdc42-Driven Tet2 Epigenetic Program.

Cancer Res 2018 07 15;78(14):3926-3937. Epub 2018 May 15.

National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Clinical Immunology Center, Chinese Academy of Medical Sciences, Beijing, China.

Dormancy is recognized as a critical biological event for tumorigenic cells surviving in an extremely harsh environment. Understanding the molecular process of dormancy can unlock novel approaches to tackle cancers. We recently reported that stem-like tumor-repopulating cells (TRC) sense mechanical signals and rapidly proliferate in a 90 Pa soft fibrin matrix. Here, we show that a stiff mechanical environment induces TRC dormancy via an epigenetic program initiated by translocation of Cdc42, a cytosolic regulator of mechanotransduction, into the nucleus, where it promotes transcription of hydroxymethylating enzyme Tet2. Tet2 epigenetically activated cell-cycle-inhibiting genes p21 and p27 to induce dormancy, but also caused downregulation of integrin β3 to maintain dormancy. This stiffness-mediated dormancy was recapitulated in mouse models for both murine and primary human melanoma TRCs. These data identify an epigenetic program directed by mechanics, which drives highly tumorigenic TRCs to enter dormancy in a stiff mechanical environment. A mechanics-directed epigenetic program enables tumor-repopulating cells to enter dormancy in a stiff mechanical environment. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-3719DOI Listing
July 2018

Publisher Correction: Chloroquine modulates antitumor immune response by resetting tumor-associated macrophages toward M1 phenotype.

Nat Commun 2018 05 1;9(1):1808. Epub 2018 May 1.

Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, 100005, Beijing, China.

In the originally published version of this Article, images in Fig. 5n were inadvertently replaced with duplicates of images in Fig. 5o during the production process. This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-018-04169-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931583PMC
May 2018

Reciprocal Signaling between Glioblastoma Stem Cells and Differentiated Tumor Cells Promotes Malignant Progression.

Cell Stem Cell 2018 04;22(4):514-528.e5

Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, CA, USA. Electronic address:

Glioblastoma is the most lethal primary brain tumor; however, the crosstalk between glioblastoma stem cells (GSCs) and their supportive niche is not well understood. Here, we interrogated reciprocal signaling between GSCs and their differentiated glioblastoma cell (DGC) progeny. We found that DGCs accelerated GSC tumor growth. DGCs preferentially expressed brain-derived neurotrophic factor (BDNF), whereas GSCs expressed the BDNF receptor NTRK2. Forced BDNF expression in DGCs augmented GSC tumor growth. To determine molecular mediators of BDNF-NTRK2 paracrine signaling, we leveraged transcriptional and epigenetic profiles of matched GSCs and DGCs, revealing preferential VGF expression by GSCs, which patient-derived tumor models confirmed. VGF serves a dual role in the glioblastoma hierarchy by promoting GSC survival and stemness in vitro and in vivo while also supporting DGC survival and inducing DGC secretion of BDNF. Collectively, these data demonstrate that differentiated glioblastoma cells cooperate with stem-like tumor cells through BDNF-NTRK2-VGF paracrine signaling to promote tumor growth.
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http://dx.doi.org/10.1016/j.stem.2018.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947947PMC
April 2018

Tumor-Repopulating Cells Induce PD-1 Expression in CD8 T Cells by Transferring Kynurenine and AhR Activation.

Cancer Cell 2018 03;33(3):480-494.e7

Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing 100005, China; Clinical Immunology Center, CAMS, Beijing 100005, China; Department of Biochemistry & Molecular Biology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China. Electronic address:

Despite the clinical successes fostered by immune checkpoint inhibitors, mechanisms underlying PD-1 upregulation in tumor-infiltrating T cells remain an enigma. Here, we show that tumor-repopulating cells (TRCs) drive PD-1 upregulation in CD8 T cells through a transcellular kynurenine (Kyn)-aryl hydrocarbon receptor (AhR) pathway. Interferon-γ produced by CD8 T cells stimulates release of high levels of Kyn produced by TRCs, which is transferred into adjacent CD8 T cells via the transporters SLC7A8 and PAT4. Kyn induces and activates AhR and thereby upregulates PD-1 expression. This Kyn-AhR pathway is confirmed in both tumor-bearing mice and cancer patients and its blockade enhances antitumor adoptive T cell therapy efficacy. Thus, we uncovered a mechanism of PD-1 upregulation with potential tumor immunotherapeutic applications.
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http://dx.doi.org/10.1016/j.ccell.2018.02.005DOI Listing
March 2018

Chloroquine modulates antitumor immune response by resetting tumor-associated macrophages toward M1 phenotype.

Nat Commun 2018 02 28;9(1):873. Epub 2018 Feb 28.

Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, 100005, China.

Resetting tumor-associated macrophages (TAMs) is a promising strategy to ameliorate the immunosuppressive tumor microenvironment and improve innate and adaptive antitumor immunity. Here we show that chloroquine (CQ), a proven anti-malarial drug, can function as an antitumor immune modulator that switches TAMs from M2 to tumor-killing M1 phenotype. Mechanistically, CQ increases macrophage lysosomal pH, causing Ca release via the lysosomal Ca channel mucolipin-1 (Mcoln1), which induces the activation of p38 and NF-κB, thus polarizing TAMs to M1 phenotype. In parallel, the released Ca activates transcription factor EB (TFEB), which reprograms the metabolism of TAMs from oxidative phosphorylation to glycolysis. As a result, CQ-reset macrophages ameliorate tumor immune microenvironment by decreasing immunosuppressive infiltration of myeloid-derived suppressor cells and Treg cells, thus enhancing antitumor T-cell immunity. These data illuminate a previously unrecognized antitumor mechanism of CQ, suggesting a potential new macrophage-based tumor immunotherapeutic modality.
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http://dx.doi.org/10.1038/s41467-018-03225-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830447PMC
February 2018

STAT3/p53 pathway activation disrupts IFN-β-induced dormancy in tumor-repopulating cells.

J Clin Invest 2018 03 12;128(3):1057-1073. Epub 2018 Feb 12.

National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, and.

Dynamic interaction with the immune system profoundly regulates tumor cell dormancy. However, it is unclear how immunological cues trigger cancer cell-intrinsic signaling pathways for entering into dormancy. Here, we show that IFN-β treatment induced tumor-repopulating cells (TRC) to enter dormancy through an indolamine 2,3-dioxygenase/kynurenine/aryl hydrocarbon receptor/p27-dependent (IDO/Kyn/AhR/p27-dependent) pathway. Strategies to block this metabolic circuitry did not relieve dormancy, but led to apoptosis of dormant TRCs in murine and human melanoma models. Specifically, blocking AhR redirected IFN-β signaling to STAT3 phosphorylation through both tyrosine and serine sites, which subsequently facilitated STAT3 nuclear translocation and subsequent binding to the p53 promoter in the nucleus. Upregulation of p53 in turn disrupted the pentose phosphate pathway, leading to excessive ROS production and dormant TRC death. Additionally, in melanoma patients, high expression of IFN-β correlated with tumor cell dormancy. Identification of this mechanism for controlling TRC dormancy by IFN-β provides deeper insights into cancer-immune interaction and potential new cancer immunotherapeutic modalities.
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http://dx.doi.org/10.1172/JCI96329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824876PMC
March 2018

[Research on the Angle and Effective Depth of Deep Acupuncture at Baliao Points by Three-dimensional Reconstruction of Computed Tomography].

Zhen Ci Yan Jiu 2017 Dec;42(6):537-41

Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing 210006.

Objective: To explore the needle insertion parameters of deep acupuncture at Baliao points for clinic and teaching.

Methods: A retrospective analysis of 100 cases of prone pelvic CT from January to June 2016 in Nanjing Hospital was carried out. The 3 D images were scanned with continuous 5 mm slice thickness. The optimum needle angle is defined as the angle of the needle along the central axis of sacral anterior and posterior hole, and the angle between the needle body and the skin surface and the center line of the body was observed. The effect needle depth is defined as the thickness of the sacral back soft tissue plus 1/2 sacral depth, to observe the best needle angle of deep acupuncture parameters of Baliao points.

Results: For deep acupuncture at Baliao, the oblique thorn method should be used with the needle-point toward the inner bottom. The best insertion angle between needle body and skin surface is: Shangliao(BL 31) (61.04±12.15)°, Ciliao(BL 32) (57.57±10.01)°, Zhongliao(BL 33) (58.25±8.69)°, Xialiao(BL 34) (54.39±10.94)°. The optimum angle of insertion between the needle body and the posterior midline of the human body is: BL 31 (24.54±6.21)°, BL 32 (18.58±7.76)°, BL 33 (17.36±7.90)°, BL 34 (30.73±9.45)°. The effective insertion depth show a decreasing trend: BL 31 (58.16±12.43) mm, BL 32 (44.57±11.55) mm, BL 33 (33.96±10.74) mm, BL 34 (31.13±10.94) mm. The effective depth is positively correlated with BMI, and has no correlation with gender and weight.

Conclusions: The study of the parameters of needle insertion should be taken into account both clinical efficacy and safety, and CT three-dimensional reconstruction can accurately, rationally and scientifically perform acupoint anatomical measurements.
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http://dx.doi.org/10.13702/j.1000-0607.2017.06.014DOI Listing
December 2017

Inhibition of ID1-BMPR2 Intrinsic Signaling Sensitizes Glioma Stem Cells to Differentiation Therapy.

Clin Cancer Res 2018 01 5;24(2):383-394. Epub 2017 Dec 5.

Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.

Normal stem cells tightly control self-renewal and differentiation during development, but their neoplastic counterparts, cancer stem cells (CSCs), sustain tumorigenicity both through aberrant activation of stemness and evasion of differentiation. Although regulation of CSC stemness has been extensively studied, the molecular mechanisms suppressing differentiation remain unclear. We performed screening and validation studies through Western blotting, qRT-PCR for treatment of WNT and SHH signaling inhibitors, and BMP signaling inducer with control and ID1-overexpressing cells. We also performed drug treatment assays with Balb/c nude mice. Inhibitor of differentiation 1 (ID1) abrogated differentiation signals from bone morphogenetic protein receptor (BMPR) signaling in glioblastoma stem cells (GSCs) to promote self-renewal. ID1 inhibited BMPR2 expression through miRNAs, miR-17 and miR-20a, which are transcriptional targets of MYC. ID1 increases MYC expression by activating WNT and SHH signaling. Combined pharmacologic blockade of WNT and SHH signaling with BMP treatment significantly suppressed GSC self-renewal and extended survival of tumor-bearing mice. Collectively, our results suggested that ID1 simultaneously regulates stemness through WNT and SHH signaling and differentiation through BMPR-mediated differentiation signaling in GSCs, informing a novel therapeutic strategy of combinatorial targeting of stemness and differentiation. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1529DOI Listing
January 2018

Cancer stem cells and differentiation therapy.

Tumour Biol 2017 Oct;39(10):1010428317729933

1 Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.

Cancer stem cells can generate tumors from only a small number of cells, whereas differentiated cancer cells cannot. The prominent feature of cancer stem cells is its ability to self-renew and differentiate into multiple types of cancer cells. Cancer stem cells have several distinct tumorigenic abilities, including stem cell signal transduction, tumorigenicity, metastasis, and resistance to anticancer drugs, which are regulated by genetic or epigenetic changes. Like normal adult stem cells involved in various developmental processes and tissue homeostasis, cancer stem cells maintain their self-renewal capacity by activating multiple stem cell signaling pathways and inhibiting differentiation signaling pathways during cancer initiation and progression. Recently, many studies have focused on targeting cancer stem cells to eradicate malignancies by regulating stem cell signaling pathways, and products of some of these strategies are in preclinical and clinical trials. In this review, we describe the crucial features of cancer stem cells related to tumor relapse and drug resistance, as well as the new therapeutic strategy to target cancer stem cells named "differentiation therapy."
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http://dx.doi.org/10.1177/1010428317729933DOI Listing
October 2017

Targeting glioma stem cells through combined BMI1 and EZH2 inhibition.

Nat Med 2017 Nov 9;23(11):1352-1361. Epub 2017 Oct 9.

Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.

Glioblastomas are lethal cancers defined by angiogenesis and pseudopalisading necrosis. Here, we demonstrate that these histological features are associated with distinct transcriptional programs, with vascular regions showing a proneural profile, and hypoxic regions showing a mesenchymal pattern. As these regions harbor glioma stem cells (GSCs), we investigated the epigenetic regulation of these two niches. Proneural, perivascular GSCs activated EZH2, whereas mesenchymal GSCs in hypoxic regions expressed BMI1 protein, which promoted cellular survival under stress due to downregulation of the E3 ligase RNF144A. Using both genetic and pharmacologic inhibition, we found that proneural GSCs are preferentially sensitive to EZH2 disruption, whereas mesenchymal GSCs are more sensitive to BMI1 inhibition. Given that glioblastomas contain both proneural and mesenchymal GSCs, combined EZH2 and BMI1 targeting proved more effective than either agent alone both in culture and in vivo, suggesting that strategies that simultaneously target multiple epigenetic regulators within glioblastomas may be effective in overcoming therapy resistance caused by intratumoral heterogeneity.
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http://dx.doi.org/10.1038/nm.4415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679732PMC
November 2017

Hippocampal TERT Regulates Spatial Memory Formation through Modulation of Neural Development.

Stem Cell Reports 2017 08 27;9(2):543-556. Epub 2017 Jul 27.

Department of Clinical Pharmacology, Institution of Stem Cells and Neuroregeneration, Pharmacy College, Nanjing Medical University, Nanjing 211166, P.R. China. Electronic address:

The molecular mechanism of memory formation remains a mystery. Here, we show that TERT, the catalytic subunit of telomerase, gene knockout (Tert) causes extremely poor ability in spatial memory formation. Knockdown of TERT in the dentate gyrus of adult hippocampus impairs spatial memory processes, while overexpression facilitates it. We find that TERT plays a critical role in neural development including dendritic development and neuritogenesis of hippocampal newborn neurons. A monosynaptic pseudotyped rabies virus retrograde tracing method shows that TERT is required for neural circuit integration of hippocampal newborn neurons. Interestingly, TERT regulated neural development and spatial memory formation in a reverse transcription activity-independent manner. Using X-ray irradiation, we find that hippocampal newborn neurons mediate the modulation of spatial memory processes by TERT. These observations reveal an important function of TERT through a non-canonical pathway and encourage the development of a TERT-based strategy to treat neurological disease-associated memory impairment.
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http://dx.doi.org/10.1016/j.stemcr.2017.06.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550029PMC
August 2017

Chemotherapeutic tumor microparticles combining low-dose irradiation reprogram tumor-promoting macrophages through a tumor-repopulating cell-curtailing pathway.

Oncoimmunology 2017;6(6):e1309487. Epub 2017 Mar 31.

Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Stem cell-like tumor-repopulating cells (TRCs) have a critical role in establishing a tumor immunosuppressive microenvironment. However, means to enhance antitumor immunity by disrupting TRCs are absent. Our previous studies have shown that tumor cell-derived microparticles (T-MPs) preferentially abrogate TRCs by delivering antitumor drugs into nuclei of TRCs. Here, we show that low dose irradiation (LDI) enhances the effect of cisplatin-packaging T-MPs (Cis-MPs) on TRCs, leading to inhibiting tumor growth in different tumor models. This antitumor effect is not due to the direct killing of tumor cells but is T cell-dependent and relies on macrophages for their efficacy. The underlying mechanism is involved in therapeutic reprograming macrophages from tumor-promotion to tumor-inhibition by disrupting TRCs and curtailing their vicious education on macrophages. These findings provide a novel strategy to reset macrophage polarization and confer their function more like M1 than M2 types with highly promising potential clinical applications.
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http://dx.doi.org/10.1080/2162402X.2017.1309487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486181PMC
March 2017

Nicotinamide metabolism regulates glioblastoma stem cell maintenance.

JCI Insight 2017 May 18;2(10). Epub 2017 May 18.

Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.

Metabolic dysregulation promotes cancer growth through not only energy production, but also epigenetic reprogramming. Here, we report that a critical node in methyl donor metabolism, nicotinamide N-methyltransferase (NNMT), ranked among the most consistently overexpressed metabolism genes in glioblastoma relative to normal brain. NNMT was preferentially expressed by mesenchymal glioblastoma stem cells (GSCs). NNMT depletes S-adenosyl methionine (SAM), a methyl donor generated from methionine. GSCs contained lower levels of methionine, SAM, and nicotinamide, but they contained higher levels of oxidized nicotinamide adenine dinucleotide (NAD+) than differentiated tumor cells. In concordance with the poor prognosis associated with DNA hypomethylation in glioblastoma, depletion of methionine, a key upstream methyl group donor, shifted tumors toward a mesenchymal phenotype and accelerated tumor growth. Targeting NNMT expression reduced cellular proliferation, self-renewal, and in vivo tumor growth of mesenchymal GSCs. Supporting a mechanistic link between NNMT and DNA methylation, targeting NNMT reduced methyl donor availability, methionine levels, and unmethylated cytosine, with increased levels of DNA methyltransferases, DNMT1 and DNMT3A. Supporting the clinical significance of these findings, NNMT portended poor prognosis for glioblastoma patients. Collectively, our findings support NNMT as a GSC-specific therapeutic target in glioblastoma by disrupting oncogenic DNA hypomethylation.
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http://dx.doi.org/10.1172/jci.insight.90019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436539PMC
May 2017
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