Roles of TGFβ1 in the expression of phosphoinositide 3-kinase isoform genes and sensitivity and response of lung telocytes to PI3K inhibitors

  • Dongli Song
  • Li Tang
  • Lu Wang
  • Jianan Huang
  • Tao Zeng
  • Hao FangEmail author
  • Xiangdong WangEmail author
Original Article



The mouse lung telocyte cell line (TCSV40) recently established provides further opportunities to learn TC biology and functions. The present study aims at investigating regulatory roles of phosphoinositide 3-kinase (PI3K) isoforms in TC proliferation and movement and in TGFβ1-induced sensitivity and response of lung TCs to PI3K inhibitors.

Materials and methods

Network and molecular interactions of genes coding PI3K family or TGFβ family proteins in mouse primary TCs were defined. Mouse lung TCSV40 proliferation, apoptosis, cell cycle, and dynamical bio-behaviors were measured with or without TGFβ1 stimulation or PI3K catalytic isoform protein (PI3K/mTOR, PI3Kα/δ/β, PI3K p110δ, or pan-PI3K) inhibitions.


The present study showed the difference of network characteristics and interactions of genes coding PI3K isoform proteins or TGFβ family proteins in primary lung telocytes from mouse lungs compared to those of other cells residing in the lung. TGFβ1 had diverse effects on TC proliferation with altered TC number in G2 or S phase, independent upon the administered dose of TGFβ1. PI3Kα/δ/β, PI3K/mTOR, and PI3K p110δ were involved in TC proliferation, of which PI3Kα/δ/β was more sensitive. The effects of pan-PI3K inhibitor indicate that more PI3K isoforms were stimulated by the administering of external TGFβ1 and contributed to TGFβ1-induced TC proliferation. PI3K p110δ upregulated TC proliferation and movement dynamically without TGFβ1, and downregulated TC proliferation with TGFβ1 stimulation, but not TC movement. PI3Kα/δ/β and PI3K/mTOR were more active in TGFβ1-induced S phase accumulation and had similar dynamic effects to PI3K p110δ. Gene expression of PI3K isoforms in TCs was upregulated after TGFβ1 stimulation. The expression of PIK3CA coding p110-α or PIK3CG coding p110-γ were up- or downregulated in TCs without TGFβ1, respectively, when PI3K/mTOR, PI3Kα/δ/β, PI3K p110δ, or pan-PI3K were inhibited. TGFβ1 upregulated the expression of PIK3CA and PIK3CB, while downregulated the expression of PIK3CD and PIK3CG.


Our data imply that TGFβ1 plays divergent roles in the expression of PI3K isoform genes in lung TCs and can alter the sensitivity and response of lung TCs to PI3K inhibitors.


Telocyte TGFβ1 Lung PI3K isoforms Cell proliferation 



phosphatidylinositol 3 -kinase


phosphoinositide-dependent protein kinase-1


proximal airway cells

CD8+ T-LL CD8+ T

cells from lung


Authors’ contributions

DS designed the study and completed the experimental process, literature search, and generation of figures. DS, HF, and XW wrote and edited the manuscript. DS, LW, LT, JNH, TZ, and HF completed the generation of figures. All authors reviewed the manuscript. All authors read and approved the final manuscript.


The work was financially supported by grants from the National Natural Science Foundation of China (81700008), the Zhongshan Distinguished Professor Grant (XDW), the National Nature Science Foundation of China (91230204, 81270099, 81320108001, 81270131, 81300010, 81700008, 81873409), the Shanghai Committee of Science and Technology (12JC1402200, 12431900207, 11410708600, 14431905100), the operation funding of Shanghai Institute of Clinical Bioinformatics, Ministry of Education for Academic Special Science and Research Foundation for PhD Education (20130071110043), and National Key Research and Development Program (2016YFC0902400, 2017YFSF090207, 2017YFC0909500).

Compliance with ethical standards

Competing interests

The authors declare that they have no competing interests.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Not applicable.

Supplementary material

10565_2019_9487_MOESM1_ESM.pdf (133 kb)
Supplement Figure 1: The effects of PI3K inhibitors on the differentiation of TCSV40 after stimulation with TGFβ1. A-D. Analysis of TCSV40 differentiation with the treatment of PI3K inhibitors. E-H. Analysis of TCSV40 differentiation with the treatment of PI3K inhibitors and stimulation with TGFβ1, n = 6-8, *P < 0.05 vs. TCSV40. #P < 0.05 vs. 5 ng/ml TGFβ1 treated TCSV40. (PNG 132 kb)
10565_2019_9487_MOESM2_ESM.pdf (133 kb)
Supplement Figure 2: The effects of PI3K inhibitors on the death of TCSV40 after stimulation with TGFβ1. A-D. Analysis of TCSV40 death with the treatment of PI3K inhibitors. E-H. Analysis of TCSV40 death with the treatment of PI3K inhibitors and stimulation with TGFβ1, n = 6-8, *P < 0.05 vs. TCSV40. #P < 0.05 vs. 5 ng/ml TGFβ1 treated TCSV40. (PNG 133 kb)


  1. Bartscht T, Rosien B, Rades D, Kaufmann R, Biersack H, Lehnerta H, et al. Inhibition of TGF-beta signaling in tumor cells by small molecule Src family kinase inhibitors. Anti Cancer Agents Med Chem. 2017;17(10):1351–6.CrossRefGoogle Scholar
  2. Bilancio A, Rinaldi B, Oliviero MA, Donniacuo M, Monti MG, Boscaino A, et al. Inhibition of p110delta PI3K prevents inflammatory response and restenosis after artery injury. Biosci Rep. 2017;37(5):BSR20171112.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Chatterjee A, Mukhopadhyay S, Tung K, Patel D, Foster DA. Rapamycin-induced G1 cell cycle arrest employs both TGF-beta and Rb pathways. Cancer Lett. 2015;360(2):134–40.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Chen W, Qin Y, Liu S. Cytokines, breast cancer stem cells (BCSCs) and chemoresistance. Clin Transl Med. 2018;7(1):27. Scholar
  5. Chiu H, Mallya S, Nguyen P, Mai A, Jackson LV, Winkler DG, et al. The Selective phosphoinoside-3-kinase p110delta inhibitor IPI-3063 potently suppresses B cell survival, proliferation, and differentiation. Front Immunol. 2017;8:747.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Cretoiu D, Xu J, Xiao J, Cretoiu SM. Telocytes and their extracellular vesicles-evidence and hypotheses. Int J Mol Sci. 2016;17(8):1322.CrossRefPubMedCentralGoogle Scholar
  7. De Angelis M, Bruselles A, Francescangeli F, Pucilli F, Vitale S, Zeuner A, et al. Colorectal cancer spheroid biobanks: multi-level approaches to drug sensitivity studies. Cell Biol Toxicol. 2018 Dec;34(6):459–69. Scholar
  8. Du L, Chen X, Cao Y, Lu L, Zhang F, Bornstein S, et al. Overexpression of PIK3CA in murine head and neck epithelium drives tumor invasion and metastasis through PDK1 and enhanced TGFbeta signaling. Oncogene. 2016;35(35):4641–52.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Du L, Lei Y, Chen J, Song H, Wu X. Potential ameliorative effects of Qing Ye Dan against cadmium induced prostatic deficits via regulating Nrf-2/HO-1 and TGF-beta1/Smad pathways. Cell Physiol Biochem. 2017;43(4):1359–68.CrossRefPubMedGoogle Scholar
  10. Ghosh D, Nandi S, Bhattacharjee S. Combination therapy to checkmate glioblastoma: clinical challenges and advances. Clin Transl Med. 2018;7(1):33. Scholar
  11. Glumac PM, LeBeau AM. The role of CD133 in cancer: a concise review. Clin Transl Med. 2018;7(1):18. Scholar
  12. Hu X, Li J, Zhang Q, Zheng L, Wang G, Zhang X, et al. Phosphoinositide 3-kinase (PI3K) isoform p110delta is essential for trophoblast cell differentiation and placental development in mouse. Sci Rep. 2016;6:28201.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Kilinc MO, Santidrian A, Minev I, Toth R, Draganov D, Nguyen D, et al. The ratio of ADSCs to HSC-progenitors in adipose tissue derived SVF may provide the key to predict the outcome of stem-cell therapy. Clin Transl Med. 2018;7(1):5. Scholar
  14. Lane RE, Korbie D, Hill MM, Trau M. Extracellular vesicles as circulating cancer biomarkers: opportunities and challenges. Clin Transl Med. 2018;7(1):14. Scholar
  15. Li D, Lo W, Rudloff U. Merging perspectives: genotype-directed molecular therapy for hereditary diffuse gastric cancer (HDGC) and E-cadherin-EGFR crosstalk. Clin Transl Med. 2018;7(1):7. Scholar
  16. Lupinacci S, Perri A, Toteda G, Vizza D, Puoci F, Parisi OI, et al. Olive leaf extract counteracts epithelial to mesenchymal transition process induced by peritoneal dialysis, through the inhibition of TGFβ1 signaling. Cell Biol Toxicol. 2019;35(2):95–109. Scholar
  17. Lv J, Wang L, Shen H, Wang X. Regulatory roles of OASL in lung cancer cell sensitivity to Actinidia chinensis Planch root extract (acRoots). Cell Biol Toxicol. 2018;34(3):207–18.CrossRefPubMedGoogle Scholar
  18. Pavlides SC, Lecanda J, Daubriac J, Pandya UM, Gama P, Blank S, et al. TGF-beta activates APC through Cdh1 binding for Cks1 and Skp2 proteasomal destruction stabilizing p27kip1 for normal endometrial growth. Cell Cycle. 2016;15(7):931–47.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Popescu LM, Gherghiceanu M, Suciu LC, Manole CG, Hinescu ME. Telocytes and putative stem cells in the lungs: electron microscopy, electron tomography and laser scanning microscopy. Cell Tissue Res. 2011a;345(3):391–403.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Popescu LM, Manole E, Serboiu CS, Manole CG, Suciu LC, Gherghiceanu M, et al. Identification of telocytes in skeletal muscle interstitium: implication for muscle regeneration. J Cell Mol Med. 2011b;15(6):1379–92.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Pridham KJ, Le L, Guo S, Varghese RT, Algino S, Liang Y, et al. PIK3CB/p110beta is a selective survival factor for glioblastoma. Neuro-Oncology. 2018;20(4):494–505.CrossRefPubMedGoogle Scholar
  22. Rusu MC, Cretoiu D, Vrapciu AD, Hostiuc S, Dermengiu D, Manoiu VS, et al. Telocytes of the human adult trigeminal ganglion. Cell Biol Toxicol. 2016;32(3):199–207.CrossRefPubMedGoogle Scholar
  23. Ryu JM, Han HJ. L-threonine regulates G1/S phase transition of mouse embryonic stem cells via PI3K/Akt, MAPKs, and mTORC pathways. J Biol Chem. 2011;286(27):23667–78.CrossRefPubMedPubMedCentralGoogle Scholar
  24. Sabnam S, Pal A. Relevance of Erk1/2-PI3K/Akt signaling pathway in CEES-induced oxidative stress regulates inflammation and apoptosis in keratinocytes. Cell Biol Toxicol. 2019.
  25. Shi L, Dong N, Ji D, Huang X, Ying Z, Wang X, et al. Lipopolysaccharide-induced CCN1 production enhances interleukin-6 secretion in bronchial epithelial cells. Cell Biol Toxicol. 2018;34(1):39–49.CrossRefPubMedGoogle Scholar
  26. Song D, Cretoiu D, Zheng M, Qian M, Zhang M, Cretoiu SM, et al. Comparison of Chromosome 4 gene expression profile between lung telocytes and other local cell types. J Cell Mol Med. 2016;20(1):71–80.CrossRefPubMedGoogle Scholar
  27. Song D, Yang D, Powell CA, Wang X. Cell-cell communication: old mystery and new opportunity. Cell Biol Toxicol. 2019a;35(2):89–93.CrossRefPubMedGoogle Scholar
  28. Song D, Xu M, Qi R, Ma R, Zhou Y, Wu D. Influence of gene modification in biological behaviors and responses of mouse lung telocytes to inflammation. J Transl Med. 2019b; in press;17:158.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Sun X, Zheng M, Zhang M, Qian M, Zheng Y, Li M, et al. Differences in the expression of chromosome 1 genes between lung telocytes and other cells: mesenchymal stem cells, fibroblasts, alveolar type II cells, airway epithelial cells and lymphocytes. J Cell Mol Med. 2014;18(5):801–10.CrossRefPubMedPubMedCentralGoogle Scholar
  30. Wang X, Cretoiu D. Telocytes: Connecting cells, Edited. Series Title: Advances in experimental medicine and biology. Published by Springer Singapore. 2016; eBook ISBN978-981-10-1061-3, Hardcover ISBN: 978-981-10-1060-6, Softcover ISBN: 978-981-10-9318-0, Series ISSN: 0065-2598, DOI:10.1007/978-981-10-1061-3.Google Scholar
  31. Wang J, Ye L, Jin M, Wang X. Global analyses of Chromosome 17 and 18 genes of lung telocytes compared with mesenchymal stem cells, fibroblasts, alveolar type II cells, airway epithelial cells, and lymphocytes. Biol Direct. 2015;10:9.CrossRefPubMedPubMedCentralGoogle Scholar
  32. Wang B, Shi L, Sun X, Wang L, Wang X, Chen C. Production of CCL20 from lung cancer cells induces the cell migration and proliferation through PI3K pathway. J Cell Mol Med. 2016;20(5):920–9.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Ye L, Song D, Jin M, Wang X. Therapeutic roles of telocytes in OVA-induced acute asthma in mice. J Cell Mol Med. 2017;21:2863–71.CrossRefPubMedPubMedCentralGoogle Scholar
  34. Yu X, Zeng T, Wang X, Li G, Chen L. Unravelling personalized dysfunctional gene network of complex diseases based on differential network model. J Transl Med. 2015;13:189.CrossRefPubMedPubMedCentralGoogle Scholar
  35. Zeng T, Zhang W, Yu X, Liu X, Li M, Chen L. Big-data-based edge biomarkers: study on dynamical drug sensitivity and resistance in individuals. Brief Bioinform. 2016;17(4):576–92.CrossRefPubMedGoogle Scholar
  36. Zhang Y, Wang L, Zhang M, Jin M, Bai C, Wang X. Potential mechanism of interleukin-8 production from lung cancer cells: an involvement of EGF-EGFR-PI3K-Akt-Erk pathway. J Cell Physiol. 2012;227(1):35–43.CrossRefGoogle Scholar
  37. Zhang W, Zeng T, Liu X, Chen L. Diagnosing phenotypes of single-sample individuals by edge biomarkers. J Mol Cell Biol. 2015;7(3):231–41.CrossRefPubMedGoogle Scholar
  38. Zhang Z, Zhang X, Zhao D, Liu B, Wang B, Yu W, et al. TGFbeta1 promotes the osteoinduction of human osteoblasts via the PI3K/AKT/mTOR/S6K1 signalling pathway. Mol Med Rep. 2019;19(5):3505–18.PubMedPubMedCentralGoogle Scholar
  39. Zheng Y, Wang X. Roles of telocytes in the development of angiogenesis. Adv Exp Med Biol. 2016;913:253–61.CrossRefPubMedGoogle Scholar
  40. Zheng Y, Li H, Manole CG, Sun A, Ge J, Wang X. Telocytes in trachea and lungs. J Cell Mol Med. 2011;15(10):2262–8.CrossRefPubMedPubMedCentralGoogle Scholar
  41. Zheng Y, Zhang M, Qian M, Wang L, Cismasiu VB, Bai C, et al. Genetic comparison of mouse lung telocytes with mesenchymal stem cells and fibroblasts. J Cell Mol Med. 2013;17(4):567–77.CrossRefPubMedPubMedCentralGoogle Scholar
  42. Zheng M, Sun X, Zhang M, Qian M, Zheng Y, Li M, et al. Variations of chromosomes 2 and 3 gene expression profiles among pulmonary telocytes, pneumocytes, airway cells, mesenchymal stem cells and lymphocytes. J Cell Mol Med. 2014a;18(10):2044–60.CrossRefPubMedPubMedCentralGoogle Scholar
  43. Zheng Y, Cretoiu D, Yan G, Cretoiu SM, Popescu LM, Fang H, et al. Protein profiling of human lung telocytes and microvascular endothelial cells using iTRAQ quantitative proteomics. J Cell Mol Med. 2014b;18(6):1035–59.CrossRefPubMedPubMedCentralGoogle Scholar
  44. Zheng Y, Cretoiu D, Yan G, Cretoiu SM, Popescu LM, Wang X. Comparative proteomic analysis of human lung telocytes with fibroblasts. J Cell Mol Med. 2014c;18(4):568–89.CrossRefPubMedPubMedCentralGoogle Scholar
  45. Zhu Y, Zheng M, Song D, Ye L, Wang X. Global comparison of chromosome X genes of pulmonary telocytes with mesenchymal stem cells, fibroblasts, alveolar type II cells, airway epithelial cells, and lymphocytes. J Transl Med. 2015;13:318.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Zhongshan Hospital Institute for Clinical Science, Shanghai Institute of Clinical Bioinformatics, Shanghai Engineering Research for AI Technology for Cardiopulmonary Diseases, Jinshan Hospital Center for Tumor Diagnosis & Therapy, Shanghai Medical CollegeFudan UniversityShanghaiChina
  2. 2.Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological SciencesChinese Academy of SciencesShanghaiChina
  3. 3.Department of Anesthesiology, Zhongshan Hospital, Department of Anesthesiology, Minhang Branch, Zhongshan HospitalFudan UniversityShanghaiChina

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