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.
This is a preview of subscription content, access via your institution
Subscribe to Journal
Get full journal access for 1 year
only $2.38 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
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.
Riely GJ, Marks J, Pao W. KRAS mutations in non-small cell lung cancer. Proc Am Thorac Soc. 2009;6:201–5.
Galon J, Bruni D. Tumor Immunology and Tumor Evolution: Intertwined Histories. Immunity. 2020;52:55–81.
Wellenstein MD, de Visser KE. Cancer-Cell-Intrinsic Mechanisms Shaping the Tumor Immune Landscape. Immunity. 2018;48:399–416.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Aktas E, Kucuksezer UC, Bilgic S, Erten G, Deniz G. Relationship between CD107a expression and cytotoxic activity. Cell Immunol. 2009;254:149–54.
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.
Raulet DH, Guerra N. Oncogenic stress sensed by the immune system: role of natural killer cell receptors. Nat Rev Immunol. 2009;9:568–80.
Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, et al. Stat3 as an Oncogene. Cell 1999;98:295–303.
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.
Cacalano NA. Regulation of Natural Killer Cell Function by STAT3. Front Immunol. 2016;7:128.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Myers JA, Miller JS. Exploring the NK cell platform for cancer immunotherapy. Nat Rev Clin Oncol. 2021;18:85–100.
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.
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.
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.
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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