bims-tubesc Biomed News
on Molecular mechanisms in tuberous sclerosis
Issue of 2022–04–17
thirteen papers selected by
  1. Atypical clinical presentation of tuberous sclerosis complex in a 53-year-old female patient.
  2. Noninvasive prenatal diagnosis based on cell-free DNA for tuberous sclerosis: A pilot study.
  3. Clinical Challenge in Urology: Management of a 11-year-old boy with Tuberous Sclerosis associated Renal Cell Carcinoma.
  4. Hierarchical cluster analysis based on disease-associated manifestations of patients with lymphangioleiomyomatosis: An analysis of the national database of designated intractable diseases of Japan.
  5. Peripheral Serum Exosomes Isolated from Patients with Acute Myocardial Infarction Promote Endothelial Cell Angiogenesis via the miR-126-3p/TSC1/mTORC1/HIF-1α Pathway.
  6. Inhibition of nonalcoholic fatty liver disease in mice by selective inhibition of mTORC1.
  7. Establishing spatial control over TORC1 signaling.
  8. The Role of mTOR and eIF Signaling in Benign Endometrial Diseases.
  9. The HOPS tethering complex is required to maintain signaling endosome identity and TORC1 activity.
  10. Role of mTOR through Autophagy in Esophageal Cancer Stemness.
  11. mTOR Signaling Pathway Regulates the Release of Proinflammatory Molecule CCL5 Implicated in the Pathogenesis of Autism Spectrum Disorder.
  12. ASPP2 Coordinates ERS-Mediated Autophagy and Apoptosis Through mTORC1 Pathway in Hepatocyte Injury Induced by TNF-α.
  13. Aging accelerates while multiparity delays tumorigenesis in mouse models of high-grade serous carcinoma.
  1. Pol Arch Intern Med. 2022 Apr 14. pii: 16243. [Epub ahead of print]
    Atypical clinical presentation of tuberous sclerosis complex in a 53-year-old female patient.
    Małgorzata Gajdzis, Paweł Gajdzis, Remigiusz Chrostek, Urszula Chrostek, Radosław Kaczmarek.
      
    DOI:  https://doi.org/10.20452/pamw.16243
  2. Mol Genet Genomic Med. 2022 Apr 16. e1952
    Noninvasive prenatal diagnosis based on cell-free DNA for tuberous sclerosis: A pilot study.
    Xiao-Yan Yang, Yan Meng, Yang-Yang Wang, Yan-Ping Lu, Qiu-Hong Wang, Yan-Qin You, Xiao-Xiao Xie, Ling Bai, Nan Fang, Li-Ping Zou.
       BACKGROUND: Noninvasive prenatal diagnosis (NIPD) based on cell-free DNA (cfDNA) has been introduced into the clinical application for some monogenic disorders but not for tuberous sclerosis (TSC) yet, which is an autosomal dominant disease caused by various variations in TSC1 or TSC2 gene. We aimed to explore the feasibility of NIPD on TSC.
    METHODS: We recruited singleton pregnancies at risk of TSC from 14 families with a proband child. Definitive NIPD for TSC was performed using targeted next-generation sequencing of cfDNA in parallel with maternal white blood cell DNA (wbcDNA). The NIPD results were validated by amniocentesis or postnatal gene testing and follow-up of the born children.
    RESULTS: Missense mutations, nonsense mutations, frameshift mutations, and splice-site variants which were obtained through de-novo, maternal, or paternal inheritance were included. The mean and minimum gestational weeks of NIPD were 17.18 ± 5.83 and 8 weeks, respectively. The NIPD results were 100% consistent with the amniocentesis or postnatal gene testing and follow-up of the born children.
    CONCLUSION: This study demonstrates that NIPD based on cfDNA is feasible for TSC, but required to be confirmed with more samples. Studies on TSC can contribute to the application and promotion of NIPD for monogenic disorders.
    Keywords:  autosomal dominant disease; cell-free DNA; monogenic disorder; noninvasive prenatal diagnosis; tuberous sclerosis
    DOI:  https://doi.org/10.1002/mgg3.1952
  3. Urology. 2022 Apr 09. pii: S0090-4295(22)00264-3. [Epub ahead of print]
    Clinical Challenge in Urology: Management of a 11-year-old boy with Tuberous Sclerosis associated Renal Cell Carcinoma.
    Danelo Estienne du Plessis, Stefan Hofmeyr, Andre van der Merwe.
      
    Keywords:  RCC; Tuberous Sclerosis; management
    DOI:  https://doi.org/10.1016/j.urology.2022.03.023
  4. Respir Investig. 2022 Apr 12. pii: S2212-5345(22)00028-4. [Epub ahead of print]
    Hierarchical cluster analysis based on disease-associated manifestations of patients with lymphangioleiomyomatosis: An analysis of the national database of designated intractable diseases of Japan.
    Mie Hayashida, Takumi Kinjo, Yosuke Wada, Yoshiaki Kitaguchi, Masayuki Hanaoka.
       BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare multisystem disease with variable manifestations and differing rates of progression among individuals. Classification of its phenotypes is an issue for consideration. We hypothesized that clinical manifestations associated with LAM cluster together and identifying these associations would be useful for identifying phenotypes.
    METHODS: Using cross-sectional data from the National Database of Designated Intractable Diseases of Japan, we performed a hierarchical cluster analysis based on disease-associated manifestations.
    RESULTS: Four clusters were identified from 404 patients (50.4% of 801 LAM patients registered in 2016). Patients in cluster 1 had only dyspnea on exertion, relatively low lung function, the earliest onset age, and the lowest prevalence of tuberous sclerosis complex (TSC). Those in cluster 2 had various manifestations with the highest prevalence of TSC. Patients in cluster 3 had major respiratory symptoms (cough, sputum, or dyspnea on exertion) or fatigue and the lowest lung function. Those in cluster 4 were asymptomatic and had the latest onset age, shortest disease duration, and relatively high prevalence of TSC. Patients in cluster 1 had the highest rate of receiving mechanistic target of rapamycin (mTOR) inhibitor treatment, suggesting that cluster 1 included those with declining lung function for which mTOR inhibitor treatment was required.
    CONCLUSIONS: Hierarchical cluster analysis based on manifestations data identified four clusters. The characteristics of cluster 1 are noteworthy in relation to the indication for mTOR inhibitor treatment. A cluster analysis of accumulated and longitudinal data that allows valid clustering and outcome comparisons is required in the future.
    Keywords:  Cluster analysis; Database; Lymphangioleiomyomatosis; Manifestation; Treatment
    DOI:  https://doi.org/10.1016/j.resinv.2022.03.003
  5. Int J Nanomedicine. 2022 ;17 1577-1592
    Peripheral Serum Exosomes Isolated from Patients with Acute Myocardial Infarction Promote Endothelial Cell Angiogenesis via the miR-126-3p/TSC1/mTORC1/HIF-1α Pathway.
    Shasha Duan, Chao Wang, Xiangli Xu, Xiaoshan Zhang, Gaofeng Su, You Li, Shuai Fu, Ping Sun, Jiawei Tian.
       Purpose: Angiogenesis is required for improving myocardial function and is a key factor in long-term prognosis after an acute myocardial infarction (AMI). Although exosomes are known to play a crucial role in angiogenesis, the role of peripheral exosomes in angiogenic signal transduction in patients with AMI remains unclear. Here, we explored the effect of exosomes extracted from the peripheral serum of AMI patients on angiogenesis and elucidated the downstream pathways.
    Patients and Methods: Serum exosomes were obtained from patients with AMI (AMI-Exo) and healthy individuals (Con-Exo). The exosomes were cocultured with human umbilical vein endothelial cells (HUVECs) in vitro, with aortic rings ex vivo, and were used to treat mouse hind-limb ischemia and mouse AMI model in vivo.
    Results: AMI-Exo raised HUVEC proliferation, tube formation, and migration, and enhanced microvessel sprouting from aortic rings compared to Con-Exo, both in vitro and ex vivo. Quantitative reverse transcription-polymerase chain reaction revealed that the abundance of miR-126-3p, a crucial regulator of angiogenesis, was increased in AMI-Exo. The inhibition of miR-126-3p decreased the benefits of AMI-Exo treatment, and miR-126-3p upregulation enhanced the benefits of Con-Exo treatment in HUVECs, aortic rings, the mouse hind-limb ischemia model, and the mouse AMI model. Knockdown and overexpression analyses revealed that miR-126-3p regulated angiogenesis in HUVECs by directly targeting tuberous sclerosis complex 1 (TSC1). Moreover, we found that miR-126-3p could inhibit TSC1 expression, which further activated mTORC1 signaling and increased HIF-1α and VEGFA expression, ultimately promoting angiogenesis.
    Conclusion: Collectively, our results provide a novel understanding of the function of exosomes in angiogenesis post AMI. We demonstrated that exosomes from the peripheral serum of AMI patients promote angiogenesis via the miR-126-3p/TSC1/mTORC1/HIF-1α signaling pathway.
    Keywords:  acute myocardial infarction; angiogenesis; exosomes; miR-126-3p; tuberous sclerosis complex 1
    DOI:  https://doi.org/10.2147/IJN.S338937
  6. Science. 2022 Apr 15. 376(6590): eabf8271
    Inhibition of nonalcoholic fatty liver disease in mice by selective inhibition of mTORC1.
    Bridget S Gosis, Shogo Wada, Chelsea Thorsheim, Kristina Li, Sunhee Jung, Joshua H Rhoades, Yifan Yang, Jeffrey Brandimarto, Li Li, Kahealani Uehara, Cholsoon Jang, Matthew Lanza, Nathan B Sanford, Marc R Bornstein, Sunhye Jeong, Paul M Titchenell, Sudha B Biddinger, Zoltan Arany.
      Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) remain without effective therapies. The mechanistic target of rapamycin complex 1 (mTORC1) pathway is a potential therapeutic target, but conflicting interpretations have been proposed for how mTORC1 controls lipid homeostasis. We show that selective inhibition of mTORC1 signaling in mice, through deletion of the RagC/D guanosine triphosphatase-activating protein folliculin (FLCN), promotes activation of transcription factor E3 (TFE3) in the liver without affecting other mTORC1 targets and protects against NAFLD and NASH. Disease protection is mediated by TFE3, which both induces lipid consumption and suppresses anabolic lipogenesis. TFE3 inhibits lipogenesis by suppressing proteolytic processing and activation of sterol regulatory element-binding protein-1c (SREBP-1c) and by interacting with SREBP-1c on chromatin. Our data reconcile previously conflicting studies and identify selective inhibition of mTORC1 as a potential approach to treat NASH and NAFLD.
    DOI:  https://doi.org/10.1126/science.abf8271
  7. J Cell Biol. 2022 May 02. pii: e202203136. [Epub ahead of print]221(5):
    Establishing spatial control over TORC1 signaling.
    Oliver Schmidt, Mariana E G de Araujo.
      Target-of-rapamycin complex 1 resides on lysosomes/vacuoles and additionally on signaling endosomes. Gao et al. (2022. J. Cell Biol.https://doi.org/10.1083/jcb.202109084) set out to define the molecular identity of signaling endosomes, along with players required for the formation and maintenance of this endosomal subpopulation.
    DOI:  https://doi.org/10.1083/jcb.202203136
  8. Int J Mol Sci. 2022 Mar 22. pii: 3416. [Epub ahead of print]23(7):
    The Role of mTOR and eIF Signaling in Benign Endometrial Diseases.
    Tatiana S Driva, Christoph Schatz, Monika Sobočan, Johannes Haybaeck.
      Adenomyosis, endometriosis, endometritis, and typical endometrial hyperplasia are common non-cancerous diseases of the endometrium that afflict many women with life-impacting consequences. The mammalian target of the rapamycin (mTOR) pathway interacts with estrogen signaling and is known to be dysregulated in endometrial cancer. Based on this knowledge, we attempt to investigate the role of mTOR signaling in benign endometrial diseases while focusing on how the interplay between mTOR and eukaryotic translation initiation factors (eIFs) affects their development. In fact, mTOR overactivity is apparent in adenomyosis, endometriosis, and typical endometrial hyperplasia, where it promotes endometrial cell proliferation and invasiveness. Recent data show aberrant expression of various components of the mTOR pathway in both eutopic and ectopic endometrium of patients with adenomyosis or endometriosis and in hyperplastic endometrium as well. Moreover, studies on endometritis show that derangement of mTOR signaling is linked to the establishment of endometrial dysfunction caused by chronic inflammation. This review shows that inhibition of the mTOR pathway has a promising therapeutic effect in benign endometrial conditions, concluding that mTOR signaling dysregulation plays a critical part in their pathogenesis.
    Keywords:  adenomyosis; eIFs; endometriosis; endometritis; mTOR signaling; typical endometrial hyperplasia
    DOI:  https://doi.org/10.3390/ijms23073416
  9. J Cell Biol. 2022 May 02. pii: e202109084. [Epub ahead of print]221(5):
    The HOPS tethering complex is required to maintain signaling endosome identity and TORC1 activity.
    Jieqiong Gao, Raffaele Nicastro, Marie-Pierre Péli-Gulli, Sophie Grziwa, Zilei Chen, Rainer Kurre, Jacob Piehler, Claudio De Virgilio, Florian Fröhlich, Christian Ungermann.
      The endomembrane system of eukaryotic cells is essential for cellular homeostasis during growth and proliferation. Previous work showed that a central regulator of growth, namely the target of rapamycin complex 1 (TORC1), binds both membranes of vacuoles and signaling endosomes (SEs) that are distinct from multivesicular bodies (MVBs). Interestingly, the endosomal TORC1, which binds membranes in part via the EGO complex, critically defines vacuole integrity. Here, we demonstrate that SEs form at a branch point of the biosynthetic and endocytic pathways toward the vacuole and depend on MVB biogenesis. Importantly, function of the HOPS tethering complex is essential to maintain the identity of SEs and proper endosomal and vacuolar TORC1 activities. In HOPS mutants, the EGO complex redistributed to the Golgi, which resulted in a partial mislocalization of TORC1. Our study uncovers that SE function requires a functional HOPS complex and MVBs, suggesting a tight link between trafficking and signaling along the endolysosomal pathway.
    DOI:  https://doi.org/10.1083/jcb.202109084
  10. Cancers (Basel). 2022 Apr 01. pii: 1806. [Epub ahead of print]14(7):
    Role of mTOR through Autophagy in Esophageal Cancer Stemness.
    Liang Du, Da Wang, Peter W Nagle, Andries A H Groen, Hao Zhang, Christina T Muijs, John Th M Plukker, Robert P Coppes.
      Esophageal cancer (EC) is a highly aggressive disease with a poor prognosis. Therapy resistance and early recurrences are major obstacles in reaching a better outcome. Esophageal cancer stem-like cells (CSCs) seem tightly related with chemoradiation resistance, initiating new tumors and metastases. Several oncogenic pathways seem to be involved in the regulation of esophageal CSCs and might harbor novel therapeutic targets to eliminate CSCs. Previously, we identified a subpopulation of EC cells that express high levels of CD44 and low levels of CD24 (CD44+/CD24-), show CSC characteristics and reside in hypoxic niches. Here, we aim to clarify the role of the hypoxia-responding mammalian target of the rapamycin (mTOR) pathway in esophageal CSCs. We showed that under a low-oxygen culture condition and nutrient deprivation, the CD44+/CD24- population is enriched. Since both low oxygen and nutrient deprivation may inhibit the mTOR pathway, we next chemically inhibited the mTOR pathway using Torin-1. Torin-1 upregulated SOX2 resulted in an enrichment of the CD44+/CD24- population and increased sphere formation potential. In contrast, stimulation of the mTOR pathway using MHY1485 induced the opposite effects. In addition, Torin-1 increased autophagic activity, while MHY1485 suppressed autophagy. Torin-1-mediated CSCs upregulation was significantly reduced in cells treated with autophagy inhibitor, hydroxychloroquine (HCQ). Finally, a clearly defined CD44+/CD24- CSC population was detected in EC patients-derived organoids (ec-PDOs) and here, MHY1485 also reduced this population. These data suggest that autophagy may play a crucial role in mTOR-mediated CSCs repression. Stimulation of the mTOR pathway might aid in the elimination of putative esophageal CSCs.
    Keywords:  autophagy; cancer stem cells; esophageal cancer; hypoxia; mTOR
    DOI:  https://doi.org/10.3390/cancers14071806
  11. Front Immunol. 2022 ;13 818518
    mTOR Signaling Pathway Regulates the Release of Proinflammatory Molecule CCL5 Implicated in the Pathogenesis of Autism Spectrum Disorder.
    Baojiang Wang, Yueyuan Qin, Qunyan Wu, Xi Li, Dongying Xie, Zhongying Zhao, Shan Duan.
      Autism spectrum disorder (ASD) is a complex pervasive neurodevelopmental disorder and neuroinflammation may contribute to the pathogenesis of ASD. However, the exact mechanisms of abnormal release of proinflammatory mediators in ASD remain poorly understood. This study reports elevated plasma levels of the proinflammatory chemokine (C-C motif) ligand 5 (CCL5) in children with ASD, suggesting an aberrant inflammatory response appearing in the development of ASD. Mining of the expression data of brain or blood tissue from individuals with ASD reveals that mTOR signaling is aberrantly activated in ASD patients. Our in vitro study shows that suppression of mTOR reduces the gene expression and release of CCL5 from human microglia, supporting that CCL5 expression is regulated by mTOR activity. Furthermore, bacterial lipopolysaccharide (LPS)-induced CCL5 expression can be counteracted by siRNA against NF-κB, suggests a determining role of NF-κB in upregulating CCL5 expression. However, a direct regulatory relationship between the NF-κB element and the mTOR signaling pathway was not observed in rapamycin-treated cells. Our results show that the phosphorylated CREB can be induced to suppress CCL5 expression by outcompeting NF-κB in binding to CREB-binding protein (CREBBP) once the mTOR signaling pathway is inhibited. We propose that the activation of mTOR signaling in ASD may induce the suppression of phosphorylation of CREB, which in turn results in the increased binding of CREBBP to NF-κB, a competitor of phosphorylated CREB to drive expression of CCL5. Our study sheds new light on the inflammatory mechanisms of ASD and paves the way for the development of therapeutic strategy for ASD.
    Keywords:  CCL5; NF-κB; autism spectrum disorder; mTOR; neurodevelopmental disorder; proinflammatory cytokines
    DOI:  https://doi.org/10.3389/fimmu.2022.818518
  12. Front Pharmacol. 2022 ;13 865389
    ASPP2 Coordinates ERS-Mediated Autophagy and Apoptosis Through mTORC1 Pathway in Hepatocyte Injury Induced by TNF-α.
    Jia Yao, Hui Yang, Han Wang, Honglin Shi, Yan Jiao, Ying Zhang, Dexi Chen, Hongbo Shi.
      Background: Though ASPP2 plays an important role in regulating cell apoptosis and autophagy in case of liver injury, there remains a lack of clarity on the molecular mechanism of ASPP2 regulating autophagy and apoptosis. Methods: A hepatocyte injury model was constructed using HL7702 cell line and TNF-α. The cells were treated by ASPP2 overexpression adenovirus or short hairpin RNA lentivirus and endoplasmic reticulum stress (ERS) or the mammalian target of rapamycin (mTOR) inhibitor or agonist, respectively. The autophagy was detected by means of western blot and Green fluorescent protein-labeled- Microtubule-associated protein light chain 3 (GFP-LC3) plasmid transfection, while the apoptosis was detected through western blot, flow cytometry and TUNEL assay. Besides, the proteins related to ERS and mTOR were detected by western blot. Results: The low level of ASPP2 expression was accompanied by high-level autophagy and low-level apoptosis and vice versa in case of hepatocyte injury induce by TNF-α. By upregulating the proteins related to mTORC1 and ERS, ASPP2 induced apoptosis but inhibited autophagy. However, the effect of ASPP2 on autophagy and apoptosis can be reversed by the use of mTORC1 and ERS interfering agent, which indicates that ASPP2 regulated autophagy and apoptosis through mTORC1and ERS pathway. ERS treatment made no difference to the expression of ASPP2 and mTOR-related proteins, which suggests the possibility that the regulation of ERS on apoptosis and autophagy could occur in the downstream of ASPP2 and mTOR. Conclusion: ASPP2 could inhibit autophagy and induce apoptosis through mTORC1-ERS pathway in case of the hepatocyte injury induce by TNF-α. The role of ASPP2-mTORC1-ERS axis was verified in hepatocyte injury, which suggests the possibility that ASPP2 is an important regulatory molecule for the survival and death of hepatocyte.
    Keywords:  ASPP2; ERS; apoptosis; autophagy; hepatocyte injury; mTORC1
    DOI:  https://doi.org/10.3389/fphar.2022.865389
  13. Gynecol Oncol. 2022 Apr 09. pii: S0090-8258(22)00212-8. [Epub ahead of print]
    Aging accelerates while multiparity delays tumorigenesis in mouse models of high-grade serous carcinoma.
    Xiaoman Hou, Yali Zhai, Kevin Hu, Chia-Jen Liu, Aaron Udager, Celeste L Pearce, Eric R Fearon, Kathleen R Cho.
       OBJECTIVES: The "incessant ovulation" hypothesis links increased risk for tubo-ovarian high-grade serous carcinoma (HGSC) due to more ovulations and reduced risk conferred by pre-menopausal exposures like oral contraceptive use, multiparity, and breastfeeding. However, most women diagnosed with HGSC are postmenopausal, implying age is a major risk factor for HGSC. Our mouse model for HGSC, based on tamoxifen (TAM)-induced somatic inactivation of the Brca1, Trp53, Rb1, and Nf1 (BPRN) tumor suppressor genes in oviductal epithelium, recapitulates key genetic, histopathologic, and biological features of human HGSCs. We aimed to credential the model for future efforts to define biological and risk modification factors in HGSC pathogenesis.
    METHODS: BPRN mice were treated with TAM to induce tumors at defined ages and parity status.
    RESULTS: BPRN mice aged 9-months prior to tumor induction had markedly shorter survival than 6-8 week old mice induced to form tumors (median 46.5 weeks versus 61.5 weeks, log-rank test P = 0.0006). No significant differences in cancer phenotypes were observed between multiparous versus nulliparous BPRN mice. However, using a modified tumor model with one wild-type Nf1 allele (BPRNfl/+), nulliparous mice had more advanced tumors than multiparous mice (Mantel-Haenszel Chi-square test of association, P = 0.01).
    CONCLUSIONS: Our findings show aging is associated with significantly shortened survival post tumor induction in the BRPN model and multiparity delays development and/or progression of HGSC in certain genetic contexts. The findings support relevance of our mouse model to gain mechanistic insights into how known factors exert their protective effects and to test novel approaches for HGSC prevention.
    Keywords:  Genetically engineered mouse model; High-grade serous carcinoma; Incessant ovulation hypothesis; Ovarian cancer
    DOI:  https://doi.org/10.1016/j.ygyno.2022.03.030
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