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PPDPF promotes lung adenocarcinoma progression via inhibiting apoptosis and NK cell-mediated cytotoxicity through STAT3

Oncogene volume 41, pages 4244–4256 (2022)Cite this article

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A Correction to this article was published on 25 July 2023

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Abstract

Lung cancer is the most common malignancy and the leading cause of cancer death worldwide, and lung adenocarcinoma (LUAD) is the most prevalent subtype. Considering the emergence of resistance to therapies, it is urgent to develop more effective therapies to improve the prognosis. Here we reported that pancreatic progenitor cell differentiation and proliferation factor (PPDPF) deficiency inhibited LUAD development both in vitro and in vivo. Mechanistically, PPDPF induces hyperactive STAT3 by interfering STAT3-PTPN1 interaction. Activated STAT3 promoted BMPR2 transcription, which further inhibited apoptosis. Moreover, PPDPF reduced NK cell infiltration and activation to develop an immunosuppressive microenvironment, which was also mediated by STAT3. Furthermore, we identified that the expression of PPDPF was positively correlated with the malignant features of LUAD, as well as BMPR2 and p-STAT3 level in clinical samples. Therefore, our study suggests that PPDPF positively regulates BMPR2 expression and facilitates immune escape via regulating STAT3 activity, providing a potential therapy target for LUAD.

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Fig. 1: PPDPF regulates the growth of lung adenocarcinoma cells both in vitro and in vivo.
Fig. 2: The role of PPDPF in lung tumorigenesis induced by KrasG12D and Trp53 loss.
Fig. 3: BMPR2 mediates the tumor-promoting effect of PPDPF.
Fig. 4: NK cells mediate the tumor-suppressive effects of PPDPF deficiency.
Fig. 5: PPDPF regulates the transcription of BMPR2 via STAT3.
Fig. 6: The activity of STAT3 is required for the tumor-promoting effect of PPDPF.
Fig. 7: PPDPF interacts with STAT3 and PTPN1.
Fig. 8: PPDPF expression is positively correlated with BMPR2 and p-STAT3 expression in clinical LUAD samples.

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Data availability

All data supporting the findings of this study are provided within the paper and its Supplementary information. All additional information will be made available upon reasonable request to the authors. Source data are provided with this paper.

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References

  1. Riely GJ, Marks J, Pao W. KRAS mutations in non-small cell lung cancer. Proc Am Thorac Soc. 2009;6:201–5.

    Article  CAS  PubMed  Google Scholar 

  2. Galon J, Bruni D. Tumor Immunology and Tumor Evolution: Intertwined Histories. Immunity. 2020;52:55–81.

    Article  CAS  PubMed  Google Scholar 

  3. Wellenstein MD, de Visser KE. Cancer-Cell-Intrinsic Mechanisms Shaping the Tumor Immune Landscape. Immunity. 2018;48:399–416.

    Article  CAS  PubMed  Google Scholar 

  4. Peters S, Reck M, Smit EF, Mok T, Hellmann MD. How to make the best use of immunotherapy as first-line treatment of advanced/metastatic non-small-cell lung cancer. Ann Oncol: Off J Eur Soc Med Oncol. 2019;30:884–96.

    Article  CAS  Google Scholar 

  5. Remark R, Becker C, Gomez JE, Damotte D, Dieu-Nosjean MC, Sautès-Fridman C, et al. The non-small cell lung cancer immune contexture. A major determinant of tumor characteristics and patient outcome. Am J Respir Crit Care Med. 2015;191:377–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Schuijs MJ, Png S, Richard AC, Tsyben A, Hamm G, Stockis J, et al. ILC2-driven innate immune checkpoint mechanism antagonizes NK cell antimetastatic function in the lung. Nat Immunol. 2020;21:998–1009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bruno A, Focaccetti C, Pagani A, Imperatori AS, Spagnoletti M, Rotolo N, et al. The proangiogenic phenotype of natural killer cells in patients with non-small cell lung cancer. Neoplasia (N. Y, NY). 2013;15:133–42.

    Article  CAS  Google Scholar 

  8. Platonova S, Cherfils-Vicini J, Damotte D, Crozet L, Vieillard V, Validire P, et al. Profound coordinated alterations of intratumoral NK cell phenotype and function in lung carcinoma. Cancer Res. 2011;71:5412–22.

    Article  CAS  PubMed  Google Scholar 

  9. Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA 3rd, Loyd JE, et al. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat Genet. 2000;26:81–4.

    Article  CAS  PubMed  Google Scholar 

  10. Soon E, Crosby A, Southwood M, Yang P, Tajsic T, Toshner M, et al. Bone morphogenetic protein receptor type II deficiency and increased inflammatory cytokine production. A gateway to pulmonary arterial hypertension. Am J Respir Crit care Med. 2015;192:859–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Peng CW, Yue LX, Zhou YQ, Tang S, Kan C, Xia LM, et al. miR-100-3p inhibits cell proliferation and induces apoptosis in human gastric cancer through targeting to BMPR2. Cancer Cell Int. 2019;19:354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jiao G, Guo W, Ren T, Lu Q, Sun Y, Liang W, et al. BMPR2 inhibition induced apoptosis and autophagy via destabilization of XIAP in human chondrosarcoma cells. Cell Death Dis. 2014;5:e1571.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Pickup MW, Hover LD, Polikowsky ER, Chytil A, Gorska AE, Novitskiy SV, et al. BMPR2 loss in fibroblasts promotes mammary carcinoma metastasis via increased inflammation. Mol Oncol. 2015;9:179–91.

    Article  CAS  PubMed  Google Scholar 

  14. Beppu H, Mwizerwa ON, Beppu Y, Dattwyler MP, Lauwers GY, Bloch KD, et al. Stromal inactivation of BMPRII leads to colorectal epithelial overgrowth and polyp formation. Oncogene 2008;27:1063–70.

    Article  CAS  PubMed  Google Scholar 

  15. Jiang Z, Song J, Qi F, Xiao A, An X, Liu N-A, et al. Exdpf is a key regulator of exocrine pancreas development controlled by retinoic acid and ptf1a in zebrafish. PLoS Biol. 2008;6:e293.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Xiao Y, Lai Y, Yu Y, Jiang P, Li Y, Wang C, et al. The Exocrine Differentiation and Proliferation Factor (EXDPF) Gene Promotes Ovarian Cancer Tumorigenesis by Up-Regulating DNA Replication Pathway. Front Oncol. 2021;11:669603.

  17. Mao Z, Li X, Ma X, Wang X, Zhang J, Fan X. Pancreatic progenitor cell differentiation and proliferation factor predicts poor prognosis in heptaocellular carcinoma. Med (Baltim). 2019;98:e14552.

  18. Liu G, Shi H, Deng L, Zheng H, Kong W, Wen X, et al. Circular RNA circ-FOXM1 facilitates cell progression as ceRNA to target PPDPF and MACC1 by sponging miR-1304-5p in non-small cell lung cancer. Biochem Biophys Res Commun. 2019;513:207–12.

    Article  CAS  PubMed  Google Scholar 

  19. Aktas E, Kucuksezer UC, Bilgic S, Erten G, Deniz G. Relationship between CD107a expression and cytotoxic activity. Cell Immunol. 2009;254:149–54.

    Article  CAS  PubMed  Google Scholar 

  20. Wang Z, Guan W, Wang M, Chen J, Zhang L, Xiao Y, et al. AML1-ETO inhibits acute myeloid leukemia immune escape by CD48. Leuk lymphoma. 2021;62:937–43.

    Article  CAS  PubMed  Google Scholar 

  21. Raulet DH, Guerra N. Oncogenic stress sensed by the immune system: role of natural killer cell receptors. Nat Rev Immunol. 2009;9:568–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, et al. Stat3 as an Oncogene. Cell 1999;98:295–303.

    Article  CAS  PubMed  Google Scholar 

  23. Schust J, Sperl B, Hollis A, Mayer TU, Berg T. Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chem Biol. 2006;13:1235–42.

    Article  CAS  PubMed  Google Scholar 

  24. Cacalano NA. Regulation of Natural Killer Cell Function by STAT3. Front Immunol. 2016;7:128.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Degos C, Heinemann M, Barrou J, Boucherit N, Lambaudie E, Savina A, et al. Endometrial Tumor Microenvironment Alters Human NK Cell Recruitment, and Resident NK Cell Phenotype and Function. Front Immunol. 2019;10:877.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lund IK, Hansen JA, Andersen HS, Møller NP, Billestrup N. Mechanism of protein tyrosine phosphatase 1B-mediated inhibition of leptin signalling. J Mol Endocrinol. 2005;34:339–51.

    Article  CAS  PubMed  Google Scholar 

  27. Zeng F, Ni E, Wang S, Lv S, Cao C, Zhang H, et al. A monoclonal antibody against the catalytic domain of PTP1B. Hybrid (2005) 2012;31:209–13.

    Article  CAS  Google Scholar 

  28. Liu M, Wang L, Sun X, Zhao X. Investigating the impact of Asp181 point mutations on interactions between PTP1B and phosphotyrosine substrate. Sci Rep. 2014;4:5095.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Liu Z, Shen J, Pu K, Katus HA, Plöger F, Tiefenbacher CP, et al. GDF5 and BMP2 inhibit apoptosis via activation of BMPR2 and subsequent stabilization of XIAP. Biochim et Biophys Acta. 2009;1793:1819–27.

    Article  CAS  Google Scholar 

  30. Nakamura T, Wang L, Wong CCL, Scott FL, Eckelman BP, Han X, et al. Transnitrosylation of XIAP regulates caspase-dependent neuronal cell death. Mol Cell. 2010;39:184–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Augeri DJ, Langenfeld E, Castle M, Gilleran JA, Langenfeld J. Inhibition of BMP and of TGFβ receptors downregulates expression of XIAP and TAK1 leading to lung cancer cell death. Mol Cancer. 2016;15:27.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Johnson DE, O’Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol. 2018;15:234–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bedel R, Thiery-Vuillemin A, Grandclement C, Balland J, Remy-Martin JP, Kantelip B, et al. Novel role for STAT3 in transcriptional regulation of NK immune cell targeting receptor MICA on cancer cells. Cancer Res. 2011;71:1615–26.

    Article  CAS  PubMed  Google Scholar 

  34. Tkach M, Coria L, Rosemblit C, Rivas MA, Proietti CJ, Díaz Flaqué MC, et al. Targeting Stat3 induces senescence in tumor cells and elicits prophylactic and therapeutic immune responses against breast cancer growth mediated by NK cells and CD4+ T cells. J Immunol . 2012;189:1162–72.

    Article  CAS  PubMed  Google Scholar 

  35. Sun X, Sui Q, Zhang C, Tian Z, Zhang J. Targeting blockage of STAT3 in hepatocellular carcinoma cells augments NK cell functions via reverse hepatocellular carcinoma-induced immune suppression. Mol Cancer Therap. 2013;12:2885–96.

    Article  CAS  Google Scholar 

  36. Sui Q, Zhang J, Sun X, Zhang C, Han Q, Tian Z. NK cells are the crucial antitumor mediators when STAT3-mediated immunosuppression is blocked in hepatocellular carcinoma. J Immunol. 2014;193:2016–23.

    Article  CAS  PubMed  Google Scholar 

  37. Ihara S, Kida H, Arase H, Tripathi LP, Chen YA, Kimura T, et al. Inhibitory roles of signal transducer and activator of transcription 3 in antitumor immunity during carcinogen-induced lung tumorigenesis. Cancer Res. 2012;72:2990–9.

    Article  CAS  PubMed  Google Scholar 

  38. Okamoto M, Liu W, Luo Y, Tanaka A, Cai X, Norris DA, et al. Constitutively active inflammasome in human melanoma cells mediating autoinflammation via caspase-1 processing and secretion of interleukin-1beta. J Biol Chem. 2010;285:6477–88.

    Article  CAS  PubMed  Google Scholar 

  39. Tulotta C, Lefley DV, Freeman K, Gregory WM, Hanby AM, Heath PR, et al. Endogenous Production of IL1B by Breast Cancer Cells Drives Metastasis and Colonization of the Bone Microenvironment. Clin Cancer Res: Off J Am Assoc Cancer Res. 2019;25:2769–82.

    Article  CAS  Google Scholar 

  40. Myers JA, Miller JS. Exploring the NK cell platform for cancer immunotherapy. Nat Rev Clin Oncol. 2021;18:85–100.

    Article  PubMed  Google Scholar 

  41. Ma N, Wang YK, Xu S, Ni QZ, Zheng QW, Zhu B, et al. PPDPF alleviates hepatic steatosis through inhibition of mTOR signaling. Nat Commun. 2021;12:3059.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank the New World Group for their Charitable Foundation to establish the Institute for Nutritional Sciences, SIBS, CAS-New World Joint Laboratory, which have given full support to this study.

Funding

This work was supported by the National Natural Science Foundation of China (82172950, 81972757), Youth Innovation Promotion Association of Chinese Academy of Sciences grant (2017324) and Sanofi-SIBS 2018 Young Faculty Award to J-JL; and the National Natural Science Foundation of China (81730083 and 82030084) to DX.

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Authors and Affiliations

  1. CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China

    Qian-Wen Zheng, Qian-Zhi Ni, Bing Zhu, Xin Liang, Yi-Kang Wang, Sheng Xu, Hui-Jun Cao, Ji Xia, Feng-Kun Zhang, Er-Bin Zhang, Xiao-Song Qiu, Xu-Fen Ding, Lin Qiu, Dong Xie & Jing-Jing Li

  2. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China

    Qian-Wen Zheng, Xiao-Song Qiu & Dong Xie

  3. Department of Thoracic Surgery, Section of Esophageal Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China

    Ning Ma & Zhi-Gang Li

  4. Department of Central Laboratory, The First Affiliated Hospital of Huzhou University, Huzhou, Zhejiang, 313000, China

    Xi-Lin Zhang

  5. Department of Critical Care Medicine, The First Affiliated Hospital of Huzhou University, Huzhou, Zhejiang, 313000, China

    Zhao-Hui Dong

  6. Department of General Surgery, Shanghai Fengxian Central Hospital, Shanghai, 201499, China

    Xue-Li Zhang

  7. NHC Key Laboratory of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment, Beijing, 100022, China

    Dong Xie

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Contributions

Conceptualization: Q-WZ, DX and J-JL; Data curation, Q-WZ, DX and J-JL; Funding acquisition, DX and J-JL; Methodology, Q-WZ, Q-ZN, BZ, XL, NM, Y-KW, SX, H-JC, JX, F-KZ, E-BZ, X-SQ, X-FD and Z-GL; Technical assistance in the flow cytometry, LQ; Patient samples collecting, X-LZ, X-LZ and Z-HD; Project administration, X-LZ, DX and J-JL; Writing—original draft, Q-WZ; Writing—review & editing, DX and J-JL. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Xue-Li Zhang, Dong Xie or Jing-Jing Li.

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Zheng, QW., Ni, QZ., Zhu, B. et al. PPDPF promotes lung adenocarcinoma progression via inhibiting apoptosis and NK cell-mediated cytotoxicity through STAT3. Oncogene 41, 4244–4256 (2022). https://doi.org/10.1038/s41388-022-02418-3

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