SPP1 induces idiopathic pulmonary fibrosis and NSCLC progression via the PI3K/Akt/mTOR pathway.

Publisher: BioMed Central Ltd Country of Publication: England NLM ID: 101090633 Publication Model: Electronic Cited Medium: Internet ISSN: 1465-993X (Electronic) Linking ISSN: 14659921 NLM ISO Abbreviation: Respir Res Subsets: MEDLINE

Publication: 2001- : London : BioMed Central Ltd.
Original Publication: London : Current Science Ltd., c2000-

Proto-Oncogene Proteins c-akt*/metabolism ; Idiopathic Pulmonary Fibrosis*/pathology ; Idiopathic Pulmonary Fibrosis*/metabolism ; Idiopathic Pulmonary Fibrosis*/genetics ; Idiopathic Pulmonary Fibrosis*/chemically induced ; Carcinoma, Non-Small-Cell Lung*/pathology ; Carcinoma, Non-Small-Cell Lung*/metabolism ; Carcinoma, Non-Small-Cell Lung*/genetics ; TOR Serine-Threonine Kinases*/metabolism ; Lung Neoplasms*/pathology ; Lung Neoplasms*/metabolism ; Lung Neoplasms*/genetics ; Osteopontin*/metabolism ; Osteopontin*/genetics ; Disease Progression* ; Phosphatidylinositol 3-Kinases*/metabolism; Humans ; Animals ; Mice ; Signal Transduction/physiology ; Mice, Inbred C57BL ; Male

Background: The prevalence of non-small cell lung cancer (NSCLC) is notably elevated in individuals diagnosed with idiopathic pulmonary fibrosis (IPF). Secreted phosphoprotein 1 (SPP1), known for its involvement in diverse physiological processes, including oncogenesis and organ fibrosis, has an ambiguous role at the intersection of IPF and NSCLC. Our study sought to elucidate the function of SPP1 within the pathogenesis of IPF and its subsequent impact on NSCLC progression.
Methods: Four GEO datasets was analyzed for common differential genes and TCGA database was used to analyze the prognosis. The immune infiltration was analyzed by TIMER database. SPP1 expression was examined in human lung tissues, the IPF fibroblasts and the BLM-induced mouse lung fibrosis model. Combined with SPP1 gene gain- and loss-of-function, qRT-PCR, Western blot, EdU and CCK-8 experiments were performed to evaluate the effects and mechanisms of SPP1 in IPF progression. Effect of SPP1 on NSCLC was detected by co-cultured IPF fibroblasts and NSCLC cells.
Results: Through bioinformatics analysis, we observed a significant overexpression of SPP1 in both IPF and NSCLC patient datasets, correlating with enhanced immune infiltration of cancer-associated fibroblasts in NSCLC. Elevated levels of SPP1 were detected in lung tissue samples from IPF patients and bleomycin-induced mouse models, with partial colocalization observed with α-smooth muscle actin. Knockdown of SPP1 inhibits TGF-β1-induced differentiation of fibroblasts to myofibroblasts and the proliferation of IPF fibroblasts. Conversely, SPP1 overexpression promoted IPF fibroblast proliferation via PI3K/Akt/mTOR pathway. Furthermore, IPF fibroblasts promoted NSCLC cell proliferation and activated the PI3K/Akt/mTOR pathway; these effects were attenuated by SPP1 knockdown in IPF fibroblasts.
Conclusions: Our findings suggest that SPP1 functions as a molecule promoting both fibrosis and tumorigenesis, positioning it as a prospective therapeutic target for managing the co-occurrence of IPF and NSCLC.
(© 2024. The Author(s).)

Biomed Res Int. 2020 Feb 10;2020:3424208. (PMID: 32104688)
Chest. 2015 Oct;148(4):1083-1092. (PMID: 26020856)
Am J Respir Crit Care Med. 2000 Jan;161(1):5-8. (PMID: 10619790)
Drug Des Devel Ther. 2019 May 31;13:1889-1900. (PMID: 31213776)
Int Immunopharmacol. 2018 Jul;60:1-8. (PMID: 29702278)
Discov Med. 2017 Feb;23(125):81-94. (PMID: 28371611)
Lancet. 2017 May 13;389(10082):1941-1952. (PMID: 28365056)
Acta Pharm Sin B. 2022 Jan;12(1):18-32. (PMID: 35127370)
Methods Mol Biol. 2017;1627:27-42. (PMID: 28836192)
Int J Mol Sci. 2019 Jan 30;20(3):. (PMID: 30704051)
Am J Respir Crit Care Med. 1997 Jan;155(1):242-8. (PMID: 9001319)
N Engl J Med. 2014 May 29;370(22):2083-92. (PMID: 24836312)
Med Sci Monit. 2019 Apr 24;25:3014-3025. (PMID: 31017126)
Biochem Biophys Res Commun. 2001 Jan 19;280(2):460-5. (PMID: 11162539)
Cancer Commun (Lond). 2023 Apr;43(4):455-479. (PMID: 36919193)
Respir Res. 2018 Feb 22;19(1):32. (PMID: 29471816)
Cell Metab. 2019 Jan 8;29(1):124-140.e10. (PMID: 30293773)
Respir Investig. 2018 Jan;56(1):72-79. (PMID: 29325685)
Biochem J. 2008 Apr 1;411(1):53-61. (PMID: 18072945)
Cancer. 1965 Mar;18:322-51. (PMID: 14264034)
Curr Atheroscler Rep. 2009 May;11(3):206-13. (PMID: 19361352)
Chin Med J (Engl). 2014;127(17):3142-9. (PMID: 25189961)
Nat Rev Cancer. 2008 Mar;8(3):212-26. (PMID: 18292776)
Respir Med. 2019 Feb;147:79-91. (PMID: 30704705)
Nat Rev Cancer. 2014 Aug;14(8):535-46. (PMID: 25056707)
Eur Respir J. 2016 Jun;47(6):1842-54. (PMID: 27030681)
Eur Respir Rev. 2019 Sep 4;28(153):. (PMID: 31484664)
Chest. 2019 Aug;156(2):383-391. (PMID: 31125557)
Am J Hum Genet. 2009 Jan;84(1):52-9. (PMID: 19100526)
J Thorac Oncol. 2011 Jan;6(1):209-17. (PMID: 21107292)
Arterioscler Thromb Vasc Biol. 2007 Nov;27(11):2302-9. (PMID: 17717292)
BMC Cancer. 2019 Jul 15;19(1):691. (PMID: 31307405)
N Engl J Med. 2014 May 29;370(22):2071-82. (PMID: 24836310)
Life Sci. 2020 Mar 15;245:117328. (PMID: 31954162)
Mol Cell Biochem. 2021 Nov;476(11):4045-4059. (PMID: 34244974)
Oncogene. 2021 Mar;40(11):2002-2017. (PMID: 33603163)
Am J Respir Crit Care Med. 2015 Nov 15;192(10):1200-7. (PMID: 26241562)
Am J Physiol Lung Cell Mol Physiol. 2015 Oct 15;309(8):L756-67. (PMID: 26320155)
Mol Carcinog. 2020 Oct;59(10):1147-1158. (PMID: 32805066)
Lancet Oncol. 2014 Feb;15(2):143-55. (PMID: 24411639)
Presse Med. 2020 Jun;49(2):104026. (PMID: 32437844)
J Cell Mol Med. 2017 Jul;21(7):1248-1259. (PMID: 28097825)
Thorac Cancer. 2012 May;3(2):150-155. (PMID: 28920300)
Nat Rev Drug Discov. 2012 Oct;11(10):790-811. (PMID: 23000686)
Int J Mol Med. 2017 Jun;39(6):1327-1337. (PMID: 28440483)

82070059 National Natural Science Foundation of China

Keywords: Fibroblasts; Idiopathic pulmonary fibrosis; Non-small cell lung cancer; PI3K/Akt/mTOR pathway; Secreted phosphoprotein 1

EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
EC 2.7.11.1 (TOR Serine-Threonine Kinases)
0 (SPP1 protein, human)
106441-73-0 (Osteopontin)
EC 2.7.1.1 (MTOR protein, human)
EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
0 (Spp1 protein, mouse)

Date Created: 20241005 Date Completed: 20241005 Latest Revision: 20241011

20250114

PMC11456247

10.1186/s12931-024-02989-7

39369217