Contribution of upregulated dipeptidyl peptidase 9 (DPP9) in promoting tumoregenicity, metastasis and the prediction of poor prognosis in non‐small cell lung cancer (NSCLC)

• Published in: International journal of cancer Vol. 140; no. 7; pp. 1620 - 1632
• Main Authors: Tang, Zhiyuan, Li, Jun, Shen, Qin, Feng, Jian, Liu, Hua, Wang, Wei, Xu, Liqin, Shi, Guanglin, Ye, Xumei, Ge, Min, Zhou, Xiaoyu, Ni, Songshi
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-04-2017; John Wiley and Sons Inc
• Subjects: Adult; Aged; Aged, 80 and over; apoptosis; Cancer; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - mortality; Cell growth; Cell Movement; Cell Proliferation; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - metabolism; DPP9; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Genes; Humans; Lung cancer; Lung Neoplasms - metabolism; Lung Neoplasms - mortality; Male; Medical prognosis; Medical research; Metastasis; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; NSCLC; Prognosis; RNA, Messenger - metabolism; RNA, Small Interfering - metabolism; S100 Calcium-Binding Protein A4 - metabolism; Survival analysis; Tissue Array Analysis; Treatment Outcome; Tumor Markers and Signatures; Vimentin - metabolism; apoptosis; NSCLC; DPP9; metastasis; prognosis
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.30571

Dipeptidyl peptidase 9 (DPP9) is encoded by DPP9, which belongs to the DPP4 gene family. Proteins encoded by these genes have unique peptidase and extra‐enzymatic functions that have been linked to various diseases including cancers. Here, we describe the expression pattern and biological function of DPP9 in non‐small‐cell lung cancer (NSCLC). The repression of DPP9 expression by small interfering RNA inhibited cell proliferation, migration, and invasion. Moreover, we explored the role of DPP9 in regulating epithelial‐mesenchymal transition (EMT). The epithelial markers E‐cadherin and MUC1 were significantly increased, while mesenchymal markers vimentin and S100A4 were markedly decreased in DPP9 knockdown cells. The downregulation of DPP9 in the NSCLC cells induced the expression of apoptosis‐associated proteins both in vitro and in vivo. We investigated the protein expression levels of DPP9 by tissue microarray immunohistochemical assay (TMA‐IHC) (n = 217). Further we found mRNA expression levels of DPP9 in 30 pairs of clinical NSCLC tissues were significantly lower than in the adjacent non‐cancerous tissues. Survival analysis showed that the overexpression of DPP9 was a significant independent factor for poor 5‐year overall survival in patients with NSCLC (p = 0.003). Taken together, DPP9 expression correlates with poor overall survival in NSCLC.
What's new?
Non‐small‐cell lung cancer (NSCLC) is associated with multiple genetic and epigenetic changes. Nonetheless, mechanisms underlying its initiation and progression are not well understood. The present study identifies a role for dipeptidyl peptidase 9 (DPP9), a DPP4 family member with suspected influence on tumor initiation and metastasis. In lung cancer cells in vitro, DPP9 repression inhibited cell proliferation, migration, and invasion, while its repression in vivo dramatically slowed tumor growth, greatly reducing tumor volume in DPP9 knockdown mice. In clinical NSCLC specimens, DPP9 upregulation was significantly associated with advanced TNM stage and was negatively prognostic for overall survival.