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We investigated the effects of cigarette smoke extract (CSE) on lung fibroblasts and found that the invasiveness of lung cancer cells was facilitated by the conditioned medium from CSE-treated fibroblasts. CSE induced autophagy in fibroblasts and increased the expression of autophagy-related proteins, including optineurin and Ras-related protein Rab1B. Afterward, the fibroblasts produced high levels of interleukin-8 (IL-8), which promoted cancer cell invasion. The inhibition of either optineurin or Rab1B abrogated a rise in microtubule-associated protein 1 light chain 3 β and a decrease in p62 protein, as well as the production of IL-8, in CSE-treated fibroblasts. A three-dimensional invasion assay using cancer cell spheroids revealed that the invasion of cancer cells alone and the fibroblast-led cancer cell invasion were both enhanced by the conditioned media from CSE-treated fibroblasts. These results suggest that cigarette smoke may induce autophagy and IL-8 secretion in lung fibroblasts and modify the microenvironment to favor invasion of lung cancer cells.

Background: Aberrant fucosylation plays a critical role in lung cancer progression. Nevertheless, the key fucosyltransferase with prognostic significance in lung cancer patients, the enzyme’s intracellular targets and complex molecular mechanisms underlying lung cancer metastasis remain incompletely understood. Methods: We performed a large-scale transcriptome-clinical correlation to identify major fucosyltransferases with significant prognostic values. Invasion, migration, cell adhesion assays were performed using lung cancer cells subject to genetic manipulation of FUT4 levels. Genome-wide RNA-seq and immunoprecipitation-mass spectrometry were used to characterize major cellular processes driven by FUT4, as well as profiling its intracellular protein targets. We also performed lung homing and metastasis assays in mouse xenograft models to determine in vivo phenotypes of high FUT4-expressing cancer cells. Findings: We show that FUT4 is associated with poor overall survival in lung adenocarcinoma patients. High FUT4 expression promotes lung cancer invasion, migration, epithelial-to-mesenchymal transition and cell adhesion. FUT4-mediated aberrant fucosylation markedly activates multiple cellular processes, including membrane trafficking, cell cycle, and major oncogenic signaling pathways. The pathway augmentation effects are independent of receptor tyrosine kinase mutations. Notably, genetic depletion of FUT4 or targeting FUT4-driven pathways diminishes lung colonization and distant metastases of lung cancer cells in mouse xenograft models. Interpretation: We propose that FUT4 can be a prognostic predictor and therapeutic target in lung cancer metastasis. Our data also offer a potential therapeutic strategy using targeted therapy in a subset of patients with high FUT4-expressing tumors with no targetable mutations. Funding Statement: Research supported by grants from Ministry of Science and Technology (MOST 107-2314-B-002 -241, MOST 105-2628-B-002 -040), and National Health Research Institutes (NHRIEX106-10610BC) in Taiwan. Declaration of Interests: The authors have no conflicts of interest to declare. Ethics Approval Statement: The study on primary tumor tissues from lung cancer patients was approved by the Institutional Review Board (IRB) of National Taiwan University Hospital (Approval No.: 201701010RINB). Written informed consent was obtained from all participants prior to inclusion in the study. Every participant was assigned a number and the data were analyzed at the group level for patient de-identification. All mice experiments were performed in compliance with an experimental protocol (20160126) approved by the NTU College of Medicine Institutional Animal Care and Use Committee (IACUC).

Background Aberrant fucosylation plays a critical role in lung cancer progression. Nevertheless, the key fucosyltransferase with prognostic significance in lung cancer patients, the enzyme's intracellular targets, and complex molecular mechanisms underlying lung cancer metastasis remain incompletely understood. Methods We performed a large-scale transcriptome-clinical correlation to identify major fucosyltransferases with significant prognostic values. Invasion, migration, cell adhesion assays were performed using lung cancer cells subject to genetic manipulation of FUT4 levels. Genome-wide RNA-seq and immunoprecipitation-mass spectrometry were used to characterize major cellular processes driven by FUT4, as well as profiling its intracellular protein targets. We also performed lung homing and metastasis assays in mouse xenograft models to determine in vivo phenotypes of high FUT4-expressing cancer cells. Findings We show that FUT4 is associated with poor overall survival in lung adenocarcinoma patients. High FUT4 expression promotes lung cancer invasion, migration, epithelial-to-mesenchymal transition, and cell adhesion. FUT4-mediated aberrant fucosylation markedly activates multiple cellular processes, including membrane trafficking, cell cycle, and major oncogenic signaling pathways. The effects are independent of receptor tyrosine kinase mutations. Notably, genetic depletion of FUT4 or targeting FUT4-driven pathways diminishes lung colonization and distant metastases of lung cancer cells in mouse xenograft models. Interpretation We propose that FUT4 can be a prognostic predictor and therapeutic target in lung cancer metastasis. Our data provide a scientific basis for a potential therapeutic strategy using targeted therapy in a subset of patients with high FUT4-expressing tumors with no targetable mutations.

Because of the expansion of aging and smoking populations, chronic obstructive pulmonary disease (COPD) is predicted to be the third leading cause of death worldwide in 2030. Therefore, it is pertinent to develop effective therapy to improve management for COPD. Cigarette smoke-mediated protease-antiprotease imbalance is a major pathogenic mechanism for COPD and results in massive pulmonary infiltration of neutrophils and macrophages, releasing excessive neutrophil elastase (NE) and matrix metalloproteinases (MMPs). Our previous studies indicated that placenta growth factor (PGF) and PGF-triggered downstream signaling molecules mediate NE-induced lung epithelial cell apoptosis, which is a major pathogenic mechanism for pulmonary emphysema. However, the relationship between MMP-directed COPD and PGF remains elusive. We hypothesize that MMPs may upregulate PGF expression and be involved in MMP-mediated pathogenesis of COPD. In this study, we demonstrate that only MMP-12 can increase the expression of PGF by increasing early-growth response protein 1 (Egr-1) level through the activation of protease-activated receptor 1 (PAR-1). The PGF-mediated downstream signaling molecules drive caspase-3 and caspase-9-dependent apoptosis in bronchial epithelial cells. Both the upregulation of PGF by MMP-12 and PGF downstream signaling molecules with pulmonary apoptosis and emphysema were also demonstrated in animals. Given these findings, we suggest that both human COPD-associated elastases, NE, and MMP-12, upregulate PGF expression and promote the progression of emphysema and COPD.

COPD is predicted to become the third leading cause of death worldwide by 2030. So far, the detailed pathogenic mechanisms of COPD are not fully understood. The cigarette smoke (CS)-trigger protease-antiprotease imbalance and chronic inflammation are crucial pathogenic mechanisms of COPD-associated SAR. CS-induced chronic inflammation is thought to be responsible for SAR. However, anti-inflammatory strategy fails to ameliorate the progression of CS-induced SAR. We proved other than CS-induced chronic inflammation, the excessive elastases upregulated PlGF, a VEGF family protein promotes angiogenesis in embryonic stage, triggers alveolar epithelial cell autophagy, apoptosis and pulmonary emphysema in mice. Whether PlGF is a pathological factor for CS-induced SAR beyond chronic inflammation is needed further investigation. Firstly, we demonstrate COPD-associated elastase, neutrophil elastase and matrix metalloproteinases-12 increased PlGF expression in lung epithelial cells. We had validated ablation of PlGF decreases the CS-induced collagen deposition in mice small airway by Masson stain (Fig. 1). Furthermore, the results of Western blot assay indicated PlGF increases mesenchymal transition markers expression but decreased epithelial markers expression. We conclude COPD-associated elastases-upregulated PlGF may play a crucial rule in CS-induced SAR progression.

Using the Serial Analysis of Gene Expression (SAGE) database from the Cancer Genome Anatomy Project, we identified heparin co-factor II (HCII), which is over-expressed in non-small cell lung cancer (NSCLC). Here, we investigated the clinical significance of HCII and provided molecular evidence to support the suggestion that HCII could enhance cancer metastasis in NSCLC. We found that high HCII expression in tumour tissue was associated with increased cancer recurrence and shorter overall survival times in 75 clinically operable NSCLC patients. High pretreatment plasma concentration of HCII was associated with reduced overall survival in 57 consecutive NSCLC patients. We over-expressed and knocked down HCII expression in lung cancer cell lines and confirmed that HCII could promote cell motility, invasion ability and filopodium dynamics in NSCLC cells in vitro and increased metastatic colonization in an in vivo mouse model. Exogenous treatment of HCII promoted cancer cell migration, and this promigratory effect of HCII was independent of thrombin. We further showed that HCII could up-regulate cancer cell migration through the activation of PI3K, which acts upstream of Rac1 and Cdc42, and this effect could be blocked by heparin. We suggest that HCII is a novel metastasis enhancer and may be used as a prognostic predictor for heparin treatment in NSCLC. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd

Rationale:Aberrant glycosylation has been known to regulate cancer cell trafficking via promoting intravascular adhesion during metastasis. Clinicopathological studies have also shown a strong correlation between aberrant glycosylation and invasive/metastatic potentials of human cancers. However, the major glycosylation enzymes that drive lung cancer metastases and the signaling networks involved in the process remain incompletely understood. Methods:We identified fucosyltransferase 4 (FUT4) as a strong predictor of patient prognosis from two independent cohorts of patients with NSCLC (TCGA and NTUH). We analyzed functional roles of FUT4 through over-expression and knock-down studies using lung cancer cell lines in vitro. Metastatic and homing potentials of FUT4-overexpressed and/or knockdown cells were evaluated in vivo in immunodeficient mice. Genome-wide RNA-seq and MS-based immune-precipitation proteomics were performed to study molecular signaling networks. Results: High expressions of FUT4 were associated with poor survivals in lung adenocarcinomas (p= 0.000681). FUT4-overexpressed lung cancer cells showed significantly increased migration, invasion, and adhesion abilities in vitro, as well as enhanced homing ability to the lungs in vivo. FUT4-overexpressedcells displayed typical characteristics of epithelial-to-mesenchymal transition (EMT) in a protein level-dependent manner. Lewis X and AAL antigens were significantly up-regulated in FUT4-overexpressedcells, which facilitated binding to E-, L- and P-selections. GSEA of RNA-seq data revealed the enrichment of metastasis-related signaling, especially in EGF and TGF-β signalings. Molecularly, FUT4 enhanced EGFR/TGFBR signaling through glycosylation of TGFBR receptors, which lead to increased binding affinity between ligands and its receptors. Conclusion: FUT4 promoted metastasis through enhancing mesenchymal phenotype mediated by glycosylated EGFR/TGFBR signaling, and through increasing binding affinity of cancer cells to selectins. High levels of FUT4 in tumor tissues significantly correlate with poor prognosis in NSCLC patients. Our study not only provided new insights into the role of FUT4 on molecular signaling as a potential therapeutic target, but also identified FUT4 as a prognostic marker in NSCLC. Note: This abstract was not presented at the meeting. Citation Format: Hsuan-Hsuan Lu, Yi-Hsiu Juan, Rueyhung Roc Weng, Shu-Yung Lin, Yen-Wei Chen, Hsin-Han Hou, Zheng-Ci Hung, Yi-Jhen Huang, Tsai-Yu Yang, Yi-Chieh Wu, Giovanni Audrey Oswita, Jin-Yuan Shih, Hsing-Chen Tsai, Chong-Jen Yu. Fucosyltransferase 4-mediated aberrant glycosylation and cell signaling networks promote lung cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1111.

Emerging evidence indicates that proteins of a disintergrin and metalloprotease (ADAM) family contribute to cancer progression and metastasis. ADAM15 is up-regulated in multiple cancers and the enzymatic activities of its extracellular metalloprotrease domain promote cancer proliferation and migration by mediating the ErbB signaling pathway. In lung cancer, the enzymatic activity of ADAM15 extracellular domain is reported to be independent of ErbB signaling, indicating an alternative mechanism in promoting lung cancer progression. However, the role of ADAM15 in non-small cell lung cancer (NSCLC) and its correlation to patient prognosis is not well understood. This study demonstrated the longest ADAM15 isoforms, isoform 6 (i6), which contained the most cytoplasmic Src homology 3 (SH3) binding motifs, was significantly up-regulated in progressive NSCLC cell. Comparison of i6 and isoform 1 (i1) revealed that the cytoplasmic domain was essential for NSCLC cell proliferation and aggressiveness. ADAM15 i6, but not i1, mediated the activation the activation of the Src homolog 2 domain containing (Shc) through physical interaction with growth factor receptor-bound protein 2 (Grb2). ADAM15 i6 overexpression promoted NSCLC cell growth in a xenograft mouse model, while ADAM15 or Grb2 knockdown resulted in tumor shrinkage. ADAM15 was overexpressed in primary NSCLC tissues compared to adjacent normal tissues. Patients with ADAM15 i6 high-expressing lung tumors had shorter survival times. Thus, a novel mechanism of the ADAM15 cytoplasmic domain is identified in NSCLC tumor progression. This may help shed light on the molecular mechanisms of ADAM proteins and facilitate development of novel therapy for NSCLC. Citation Format: Hsin-Han Hou. A disintergrin and metalloprotease (ADAM) 15 promotes non-small cell lung cancer (NSCLC) proliferation through cytosolic domain, not extra-cytosolic metalloprotease activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 542.

Emerging evidence has indicated that proteins of a disintergrin and metalloprotease (ADAM) family contribute to cancer progression and metastasis. One member of this family, ADAM15, has been shown to be upregulated in multiple cancers, including gastric, lung, breast, and prostate cancers, and the enzymatic activities of its extracellular metalloprotrease domain promote breast cancer proliferation and migration through mediating ErbB signaling pathway. The patients with ADAM15 high-expressing lung tumors have shorter survival time and ADAM15 has been proved to enhance synovial fibroblasts anti-apoptosis ability via focal adhesion kinase signaling pathway. We firstly demonstrated other than extracellular enzymetic activity, the longest isoform of ADAM15 (ADAM15 i6), which contains the most cytoplasmic Src homology 3 (SH3) binding motifs, significantly upregulated in primary lung cancer tissues and promoted NSCLC proliferation via growth factor receptor-bound protein 2 (Grb2) and Src homolog 2 domain containing (Shc) association. In this study, we further explore the roles of ADAM15 cytosolic domain in NSCLC apoptosis resistance. Overexpression of ADAM15 i6 promoted CL1-0 cell anti-apoptosis ability according to the trypan blue inclusion assay. Ablation of nephrocystin (NPHP1) attenuated the ADAM15 i6-promoted anti-apoptosis ability. Thus, we identified a novel mechanism of the ADAM15 cytoplasmic domain in NSCLC tumor progression, which will shed light on the molecular mechanisms of ADAM proteins, and facilitate development of novel therapy in NSCLC. Note: This abstract was not presented at the meeting. Citation Format: Hsin-Han Hou, Chong-Jen Yu. The cytosolic domain of a disintergrin and metalloprotease (ADAM) 15 promotes non-small cell lung cancer (NSCLC) anti-apoptosis ability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 538. doi:10.1158/1538-7445.AM2017-538

Background Chronic pulmonary obstructive disease (COPD) has become the fourth leading cause of death worldwide. Cigarette smoking induces neutrophil elastase (NE) and contributes to COPD, but the detailed mechanisms involved are not fully established. In an animal model of pulmonary emphysema, there are increased expressions of placenta growth factor (PlGF) and lung epithelial (LE) cell apoptosis. This study hypothesized that excessive NE may up-regulate PlGF and that PlGF-induced LE apoptosis mediates the pathogenesis of pulmonary emphysema. Methods Human bronchial epithelial cells, BEAS-2B, and primary mouse type II alveolar epithelial cells were treated with NE. The PlGF promoter activity was examined by luciferase activity assay, while PlGF expression and secretion were evaluated by RT-PCR, Western blotting, and ELISA. Both cell lines were treated with PlGF to evaluate its effects and the downstream signaling pathways leading to LE cell apoptosis. PlGF knockout and wild-type mice were instilled with NE to determine the roles of PlGF and its downstream molecules in NE-promoted mice pulmonary apoptosis and emphysema phenotype. Results The transcriptional factor, early growth response gene-1, was involved in the NE-promoted PlGF promoter activity, and the expression and secretion of PlGF mRNA and protein in LE cells. PlGF-induced LE cell apoptosis and NE-induced mice pulmonary apoptosis and emphysema were mediated by the downstream c-Jun N-terminal kinase (JNK) and protein kinase C (PKC)δ signaling pathways. Conclusion The NE-PlGF-JNK/PKCδ pathway contributes to the pathogenesis of LE cell apoptosis and emphysema. PlGF and its downstream signaling molecules may be potential therapeutic targets for COPD. Electronic supplementary material The online version of this article (doi:10.1186/s12931-014-0106-1) contains supplementary material, which is available to authorized users.

Emerging evidence has indicated that proteins of a disintergrin and metalloprotease (ADAM) family contribute to cancer progression and metastasis. One member of this family, ADAM15, has been shown to be upregulated in multiple cancers, including gastric, lung, breast, and prostate cancers, and the enzymatic activities of its extracellular metalloprotrease domain promote breast cancer proliferation and migration through mediating ErbB signaling pathway. The patients with ADAM15 high-expressing lung tumors have shorter survival time and enzymatic activity of ADAM15 extracellular domain activates MMP-9 and promotes NSCLC migration and invasion. We firstly demonstrated other than extracellular enzymetic activity, the longest isoform of ADAM15 (ADAM15 i6), which contains the most cytoplasmic Src homology 3 (SH3) binding motifs, significantly upregulated in primary lung cancer tissues and promoted NSCLC proliferation via growth factor receptor-bound protein 2 (Grb2) and Src homolog 2 domain containing (Shc) association. In this study, we further explore the roles of ADAM15 cytosolic domain in NSCLC invasion and migration. Overexpression of ADAM15 i6 promoted CL1-0 cell invasion and migration according to the transwell and wound healing assay. Ablation of Ras protein activator (RASA)1 and protein tyrosine kinase (PTK)6 attenuated the ADAM15 i6-promoted invasion and migration respectively. Thus, we identified a novel mechanism of the ADAM15 cytoplasmic domain in NSCLC tumor progression, which will shed light on the molecular mechanisms of ADAM proteins, and facilitate development of novel therapy in NSCLC. Citation Format: Hsin-Han Hou, Chong-Jen Yu. The cytosolic domain of a disintergrin and metalloprotease (ADAM) 15 promotes non-small cell lung cancer (NSCLC) invasion and migration. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1166.

Emerging evidence has indicated that proteins of a disintergrin and metalloprotease (ADAM) family contribute to cancer progression and metastasis. One member of this family, ADAM15, was reported to over-express in multiple cancers, including gastric, lung, breast, and prostate cancers. It has been shown that the enzymatic activities of its extracellular metalloprotease domain mediate ErbB signaling pathway and promote breast cancer proliferation and migration. Nevertheless, in non-small cell lung cancer (NSCLC), the role of ADAM15 and its correlation to patient prognosis is still not well understood. Moreover, unlike in breast cancer, the enzymatic activities of the ADAM15 extracellular domain appeared to be independent of ErbB signaling and lung cancer proliferation, indicating an alternative mechanism of ADAM15 in promoting lung cancer progression. Here, we demonstrated that ADAM15 was over-expressed in primary NSCLC tissues compared to the adjacent normal tissues. Patients with ADAM15 high-expressing lung tumors had shorter survival times. Furthermore, we examined different isoforms of ADAM15 and discovered that, isoform 6 (i6), which contains the most cytoplasmic Src homology 3 (SH3) binding motifs, was significantly upregulated in primary lung cancer tissues. Comparison of i6 and isoform 1 (i1), which has no cytoplasmic SH3 binding motifs, revealed that the cytoplastmic domain is essential for lung cancer proliferation, as well as aggressiveness in an in vitro lung cancer migration model. We also showed that ADAM15 i6, but not i1, mediated ErbB signaling pathway through physical interaction with growth factor receptor-bound protein 2 (Grb2), and activation of Src homolog 2 domain containing (Shc). Most importantly, overexpression of ADAM15 i6 promoted NSCLC cell growth in a xenograft mouse model while knockdown of i6 resulted in tumor shrinkage. Thus, we identified a novel mechanism of the ADAM15 cytoplasmic domain in NSCLC tumor progression, which will not only shed light on the molecular mechanisms of ADAM proteins, but also facilitate development of novel therapy in NSCLC. Citation Format: Hsin-Han Hou. The cytosolic domain of a disintergrin and metalloprotease (ADAM) 15 promotes non-small cell lung cancer (NSCLC) proliferation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4948. doi:10.1158/1538-7445.AM2015-4948

Lung cancer is the leading cause of cancer-related deaths in worldwide, including in Taiwan. Lung cancer can typically be grouped into two large categories: small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), which account for 15% and 85% of lung cancers, respectively. Despite the continuing endeavors by scientists and clinicians, the cure rate remains low and there is urgent to develop a novel target for NSCLC therapy. The a disintegrin and metalloprotease (ADAM)-15 is a transmembrane protease mediating a wide variety of activities including proteolysis, adhesion, cell fusion and signaling. The expression of ADAM-15 is significantly up-regulated in NSCLC compared to normal tissue. However, the mechanisms of ADAM-15-modulated tumorigenesis in NSCLC are remained unclear. The external enzymetic activity of ADAM15 doesn’t involve in the common pathways in tumoregenesis of NSCLC, such as HER3-EGFR signaling. ADAM15 isoforms are different in cytoplasmic tails, which may drive different biological behavior through intracellular signaling. Therefore, we hypothesized that the diverse cytosolic domain of ADAM15 isoforms plays a crucial role in tumoregenesis of NSCLC. In this study, using real-time quantitative PCR measuring the mRNA expression of 22 ADAMs in NSCLC, we identified a correlation of higher expression of ADAM15 in NSCLC of non-smokers (p=0.002, compared with ex- and current smokers) and in adenocarcinoma (p=0.038, compared with squamous cell ca). Comparing to non-invasive CL1-0 cells and matched normal tissue, CL1-5 cells and NSCLC tissue expressed more the longest ADAM-15 isoform with the largest amount of Src homology (SH)3-binding domain. The association ADAM-15 with SH3-motif containing protein, growth factor receptor-bound (Grb) 2, promoted the ability of proliferation in NSCLC in vitro and in vivo. In conclusion, we suggested that the cytosolic domain of ADAM-15 promotes proliferation of NSCLC via enhance of Grb2-associated signaling pathways, and the inhibition of ADAM-15 may be a potential therapeutic target for NSCLC. Citation Format: Hsin-Han Hou, Chong-Jen Yu. The cytosolic domain of a disintegrin and metalloprotease (ADAM)-15 promotes proliferation of non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3317. doi:10.1158/1538-7445.AM2014-3317

Chronic pulmonary obstructive disease (COPD) is the fourth leading cause of death worldwide, however, the pathogenic factors and mechanisms are not fully understood. Pulmonary emphysema is one of the major components of COPD and is thought to result from oxidative stress, chronic inflammation, protease–antiprotease imbalance and lung epithelial (LE) cell apoptosis. In our previous studies, COPD patients were noted to have higher levels of placenta growth factor (PlGF) in serum and bronchoalveolar lavage fluid than controls. In addition, transgenic mice overexpressing PlGF developed pulmonary emphysema and exposure to PlGF in LE cells induced apoptosis. Furthermore, intratracheal instillation of porcine pancreatic elastase (PPE) on to PlGF wild type mice induced emphysema, but not in PlGF knockout mice. Therefore, we hypothesized that PPE generates pulmonary emphysema through the upregulation of PlGF expression in LE cells. The elevation of PlGF then leads to LE cell apoptosis. In the present study, we investigated whether PPE induces PlGF expression, whether PlGF induces apoptosis and whether the downstream mechanisms of PlGF are related to LE cell apoptosis. We found that PPE increased PlGF secretion and expression both in vivo and in vitro. Moreover, PlGF-induced LE cell apoptosis and PPE-induced emphysema in the mice were mediated by c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) pathways. Given these findings, we suggest that the increase in PlGF and PlGF-induced JNK and p38 MAPK pathways contribute to PPE-induced LE cell apoptosis and emphysema. Regulatory control of PlGF and agents against its downstream signals may be potential therapeutic targets for COPD.